CYCLOPHOSPHAMIDE
CYCLOPHOSPHAMIDE
CASRN: 50-18-0
http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~AAA2IaWOB:3
Human Health Effects:
Evidence for Carcinogenicity:
Classification of carcinogenicity: 1) evidence
in humans: sufficient; 2) evidence in animals: sufficient. Overall summary
evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic
to humans. /From table/
The Carcinogen Assessment Group in EPA's
Research and Development Office has evaluated cyclophosphamide for
carcinogenicity. According to their analysis, the weight of evidence for
cyclophosphamide is group C, which is based on inadequate evidence in humans and
limited evidence in animals. As a group C chemical, cyclophosphamide is
considered a possible human carcinogen.
Human Toxicity Excerpts:
LIMB REDUCTION DEFECTS HAVE BEEN OBSERVED IN
TWO CASES OF INFANTS EXPOSED TO CYCLOPHOSPHAMIDE IN UTERO. ONE MOTHER RECEIVED
100 MG/DAY DURING HER ENTIRE PREGNANCY: HER INFANT HAD NO BIG TOES OR THEIR
RESPECTIVE METATARSALS AND PHALANGES; THE LEFT FIFTH FINGER HAD A HYPOPLASTIC
MIDPHALANGE; THE INFANT ALSO HAD A PROMINENT PALATAL GROOVE. /MONOHYDRATE/
Paternal use of cyclophosphamide prior to
conception has been associated with cardiac & limb abnormalities in an
infant.
Cyclophosphamide crosses the placenta. Use in
humans has resulted in both normal & malformed (missing fingers &/or
toes, cardiac anomalies, hernias) newborns; risk seems to be less in the second
& third trimesters. Low birth weight is also a risk with exposure of the
fetus to antineoplastics. First trimester: It is usually recommended that use of
antineoplastics, especially combination chemotherapy, be avoided whenever
possible, especially during the first trimester. Although information is limited
because of the relatively few instances of antineoplastic admin during
pregnancy, the mutagenic, teratogenic, & carcinogenic potential of these
medications must be considered. Other hazards to the fetus include adverse
reactions seen in adults.
... A treated mother gave birth to a 1900 g
infant with multiple anomalies including 4 toes on each foot, flattening of the
nasal bridge & a hypoplastic 5th finger. The clinical picture was compatible
with fetal injury occurring during an intensive course of iv therapy (1,800 mg)
given at about the 77th to 82nd day of gestation.
Patients who receive high dose of
cyclophosphamide over prolonged periods may develop interstitial pulmonary
fibrosis, which can be fatal. In some cases, discontinuance of the drug and
administration of corticosteriods has failed to reverse this syndrome.
Cardiotoxicity, which is uncommon at usual
dosages, has been reported in patients receiving high doses of cyclophosphamide
(120 (i.e., 60 mg/kg daily) to 270 mg/kg over a period of a few days), generally
as part of an intensive, multiple-drug antineoplastic regimen or in conjunction
with transplantation procedures. Potentially fatal cardiotoxicity also has
occurred when cyclophosphamide (given concomitantly with mesna /2-mercaptoethane
sulfonic acid sodium salt/ and followed with autologous bone marrow transplant)
was administered inadvertently in a dosage of 4 g/sq m daily for 4 doses rather
than in a total dose of 4 g/sq m administered over 4 days in equally divided
doses of 1 g/sq m daily as part of a phase I protocol. Deaths have occurred from
diffuse hemorrhagic myocardial necrosis and from a syndrome of acute
myopericarditis when cyclophosphamide was used in high doses alone or in
combination regimens; severe, sometimes fatal congestive heart failure has
occurred rarely within a few days after the first dose of cyclophosphamide in
such cases. Hemopericardium secondary to hemorrhagic myocarditis and myocardial
necrosis, and pericarditis without evidence of hemopericardium, also has been
reported.
Sister chromatid exchanges (SCE) and
lymphocyte subsets of children with acute lymphoblastic leukemia (ALL) were
investigated during chemotherapy. The treatment followed protocol ALL-BFM-90.
Children with ALL at the time of diagnosis showed statistically significant
higher SCE frequencies (4.9 + or - 0.77) than healthy controls (3.6 + or - 0.93;
P = 0.002). The in vivo effects of cyclophosphamide (CP) resulted in a dramatic
increase of the SCE frequency (20.5 + or - 3.76). This increased SCE level of
lymphocytes might reflect an instability of DNA or a deficiency of DNA repair.
One could suggest that lymphocytes of children with ALL might have a higher
susceptibility to harmful influences; and this could be a co-factor towards the
development of the malignant disease. However, immediately 1 wk after the admin
of CP, the SCE rate decreased. This decline of SCE frequency correlated with a
severe reduction of the absolute number of T lymphocytes. The observed reduction
of SCE frequency may be due to a loss of T lymphocytes, or SCE became repaired
during 1 week.
In the present study a cancer risk assessment
of occupational exposure to cyclophosphamide (CP), a genotoxic carcinogenic
antineoplastic agent, was carried out following two approaches based on (1) data
from an animal study and (2) data on primary and secondary tumors in CP-treated
patients. Data on the urinary excretion of CP in health care workers were used
to estimate the uptake of CP, which ranged from 3.6 to 18 ug/day. Based on data
from an animal study, cancer risks were calculated for a health care worker with
a body weight of 70 kg and a working period of 40 yr, 200 days/yr (linear
extrapolation). The life-time risks (70 yr) of urinary bladder cancer in men and
leukemias in men and women were found to be nearly the same and ranged from 95
to 600 per million. Based on the patient studies, cancer risks were calculated
by multiplication of the 10-yr cumulative incidence per gram of CP in patients
by the estimated mean total uptake in health care workers over 10 yr, 200
days/yr. The risk of leukemias in women over 10 yr ranged from 17 to 100 per
million using the secondary tumor data (linear extrapolation). Comparable
results were obtained for the risk of urinary bladder tumors and leukemias in
men and women when primary tumor data were used. Thus, on an annual basis,
cancer risks obtained from both the animal and the patient study were nearly the
same and ranged from about 1.4 to 10 per million. In The Netherlands it is
proposed that, for workers, a cancer risk per cmpd of one extra cancer
case/million/year should be striven for ("target risk") and that no
risk higher than 100/million/year ("prohibitory risk") should be
tolerated.
Cyclophosphamide ... commonly cause a severe
hemorrhagic cystitis in acute overdose. Nausea and vomiting occur acutely due to
destruction of the intestinal epithelium. Myelosuppression with resultant
leukopenia, anemia, and variable thrombocytopenia has been reported. Leukocyte
counts fall within 1 week after therapeutic treatment; platelets decline soon
afterward. Maximum depression occurs in 2-3 weeks, followed by quick recovery.
Hair and hearing loss with tinnitus have been reported.
Alkylating agents are cytotoxic and kill
rapidly dividing neoplastic and normal cells and have drastic effects on cells
of the immune system. ... In cancer patients, a high CY dose (1000 mg/sq m
intravenously (iv)) results in 30 and 40% reduction of B and T cells,
respectively, after 7 days ... . A low CY dose (300 mg/sq m iv), on the
contrary, had no effect on the number of B and T cells. /Alkylating agents/
A newborn exposed in utero to cyclophosphamide
during the 1st trimester presented with multiple anomalies. the mother, who was
being treated for a severe exacerbation of systemic lupus erythematosus,
received 2 IV doses of 200 mg each between 15 & 46 days' gestation. Except
for prednisone, 20 mg/day, no other medication was given during the pregnancy.
The 3150 g female infant was delivered at 39 wk gestational age with multiple
abnormalities, including dysmorphic facies, multiple eye defects including
bilateral blepharophimosis with left microphthalmos, abnormally shaped. low-set
ears, cleft palate, bilaterally absent thumbs, & dystrophic nails.
Borderline microcephaly, hypotonia, & possible developmental delay were
observed at 10 months of age.
Cyclophosphamide is one of the most common
causes of chemotherapy-induced menstrual difficulties & azoospermia.
Permanent secondary amenorrhea with evidence of primary ovarian damage has been
observed after long-term (20 months) use of cyclophosphamide. In contrast,
successful pregnancies have been reported following high-dose therapy. Moreover,
azoospermia appears to be reversible when the drug is stopped.
Cyclophosphamide-induced chromosomal
abnormalities are also of doubtful clinical significance but have been described
in some patients after use of the drug. A study published in 1974 reported
chromosome abnormalities in patients treated with cyclophosphamide for
rheumatoid arthritis & scleroderma. In contrast, chromosome studies were
normal in a mother & infant treated during the 2nd & 3rd trimesters in
another report. In another case, a 34 yr old woman with acute lymphoblastic
leukemia was treated with multiple antineoplastic agents form 22 wk gestation
until delivery of a healthy female infant 18 wk later. Cyclophosphamide was
admin 3 times between the 26th & 30th wks of gestation. Chromosome analysis
of the newborn revealed a normal karyotype (46,XX) but with gaps & a ring
chromosome. The clinical significance of these finding sin unknown, but since
these abnormalities may persist for several years, the potential existed for an
increased risk of cancer as well as for a risk of genetic damage in the next
generation.
A study published in 1985 examined 30 men to
determine the effect of cyclophosphamide on male hormone levels &
spermatogenesis. The men had been treated at a mean age of 9.4 yr for a mean
duration of 280 days. The mean age of the men at the time of the study was 22
yrs with a mean interval form end of treatment to evaluation of 12.8 yrs. Four
of the men were azoospermic, 9 were oligospermic, & 17 were normospermic.
Compared to normal controls, however, the 17 men classified as normospermic had
lower ejaculate volumes (3.1 vs. 3.3 ml), lower sperm density (54.5*10^6 vs.
79*10^6/ml), decreased sperm motility (42% vs. 61%, p<0.05), & less
normal sperm forms (61% vs. 70%, p<0.05). concns of testosterone,
dehydroepiandrosterone sulfate, & prolactin were not significantly different
between patients & controls. One oligospermic man (sperm density 12*10^6/ml)
had fathered a child.
A 1979 report involved a case of an 18 yr old
woman with Burkitt lymphoma diagnosed in the 26th wk of gestation. She was
treated with a 7 day course of cyclophosphamide, 10 mg/kg/day IV, as a single
daily dose (total dose 3.5 g). Six weeks after the last chemotherapy dose, she
delivered a normal, 2160 g male infant. Analysis of the newborn's blood counts
was not conducted. The tumor recurred in the postpartum period, & treatment
with cyclophosphamide, 6 mg/kg/day IV, was started 20 days after delivery.
Although she was advised not to nurse her infant, she continued to do so until
her sudden death after the third dose of cyclophosphamide. Blood counts were
conducted on both the mother & the infant during therapy. Immediately prior
to the first dose, the infant's leukocyte & platelet counts were 4,800/cu mm
(abnormally low for age) & 270,000/cu mm, respectively. After the third
maternal dose, the infant's counts were 3,200/cu mm & 47,000/cu mm,
respectively. Both counts were interpreted by the investigator as signs of
cyclophosphamide-induced toxicity. It was concluded that breast feeding should
be stopped during therapy with the agent.
Chemotherapy induced pulmonary toxicity:
Cyclophosphamide. Histopathology: endothelial swelling, pneumocyte dysplasia,
lymphocyte infiltration; fibrosis. Clinical features: Does not appear to be
schedule- or does-related & may occur after discontinuation. Clinical
presentation: progressive dyspnea, fever, dry cough, tachypnea, fine rales, decr
diffusing capacity & restrictive ventilatory defect, bilateral interstitial
infiltrates. Treatment/Outcome: Clinical recovery reported in about 50% of
patients within 1-8 wk if therapy stopped. Some of these patients received
steroid therapy; however, others have died despite steroid therapy.
Occasionally, therapy has been restated without recurrence. /from table/
Two patients received four times the lethal
dose of cyclophosphamide: one died & the other has residual cardiac damage.
In order to develop a method for detecting
metabolism-mediated embryotoxicity, differentiating embryonic stem (ES) cells
were exposed to the well-known proteratogen, cyclophosphamide (CPA). CPA was
tested in a scientifically validated embryonic stem-cell test (EST), and in the
newly developed reporter-gene assay for developmental cardiotoxicity. Both
assays gave false-negative results. Because no metabolic competence (cytochrome
P450 activity) was found in the ES cells under the selected culture conditions,
a simple biotransformation system was combined with the reporter-gene assay. As
the metabolic pathway of CPA is well characterised, the genetically engineered
mammalian cell line V79, transfected with CYP2B1 cDNA, was selected as a
biotransformation system. CYP2B1 is responsible for transforming CPA into
teratogenically active metabolites. The supernatants of genetically engineered
V79 cells were analysed in the reporter-gene assay for developmental
cardiotoxicity. In preliminary experiments, the combined system was able to
detect the embryotoxic potential of the proteratogen, CPA.
A 3 hr exposure time, in both the absence
& presence of metabolic activation, was used for the in vitro Comet assay.
...The Comet assay & the chromosomal aberration tests was found to be
satisfactory on a qualitative basis, although positive results in the Comet
assay were always at higher doses than in the cytogenetic test.
These studies enable the pattern of emesis and
nausea for 3 days following high-dose cyclophosphamide to be described and give
some insight into the mechanisms of emesis which may be operating. Nausea and
vomiting induced by cyclophosphamide-based chemotherapy has long latency of
onset (8-13 hr) and continues for at least 3 days. These findings are of
particular importance as many of these patients receive chemotherapy as
outpatients and emphasize the need for appropriate anti-emetic prophylaxis for
patients at home. Ondansetron was extremely effective over this time in the
control of emesis and nausea. These results suggest that high-dose
cyclophosphamide-induced emesis over days 1-3 is largely mediated via
5-hydroxytryptamine (5-HT) and 5-HT3 receptors.
Skin, Eye and Respiratory Irritations:
A powerful skin irritant.
Drug Warnings:
Appropriate caution is advised when the drug
is considered for use in ... /nonneoplastic/ conditions, not only because of its
acute toxic effects but also because of its high potential for inducing
sterility, teratogenic effects, & leukemia. ... Administration of the drug
should be interrupted at the first indication of dysuria or hematuria. The
syndrome of inappropriate secretion of antidiuretic hormone (ADH) has been
observed in patients receiving cyclophosphamide, usually at doses higher than 50
mg/kg. It is important to be aware of the possibility of water intoxication,
since these patients are usually vigorously hydrated.
POTENTIAL ADVERSE EFFECTS ON FETUS: Various
fetal malformations, especially skeletal defects and dysmorphic features, but
other chemotherapeutic agents given concurrently. POTENTIAL SIDE EFFECTS ON
BREAST-FED INFANT: Transient neutropenia from cyclophosphamide with prednisone
and vincristine. Potential mutagenicity, carcinogenicity, adverse effects on
fetus. FDA Category: D (D = There is evidence of human fetal risk, but the
potential benefits from use in pregnant women may be acceptable despite the
potential risks (e.g., if the drug is needed in a life-threatening situation or
for a serious disease for which safer drugs cannot be used or are ineffective.))
/from Table II/
Drugs that are Contraindicated during
Breast-Feeding: Cyclophosphamide: Possible immune suppression; unknown effect on
growth or association with carcinogenesis; neutropenia. /from Table 1./
THE DRUG IS MOST TOXIC TO THE HUMAN FETUS
DURING 1ST 3 MO & CONGENITAL ABNORMALITIES HAVE BEEN DETECTED AFTER IV
INJECTION OF LARGE DOSES TO PREGNANT WOMEN DURING THIS PERIOD OF PREGNANCY.
/MONOHYDRATE/
For routine clinical use, ample fluid intake
is recommended.
Cyclophosphamide is distributed into breast
milk. Breast-feeding is not recommended during chemotherapy because of the risks
to the infant (adverse effects, mutagenicity, carcinogenicity).
Prepubescent girls treated with
cyclophosphamide usually develop secondary sexual characteristics normally, have
regular menses, and subsequently conceive; however, ovarian fibrosis and
apparent complete loss of germ cells after prolonged treatment in late
prepubescence have been reported. Prepubescent boys treated with
cyclophosphamide develop secondary sexual characteristics normally, but may have
oligospermia or azoospermia, increased gonadotropin secretion, and some degree
of testicular atrophy; azoospermia may be reversible, although possibly not for
several years after the end of cyclophosphamide therapy.
Although appropriate studies on the
relationship of age to the effects of cyclophosphamide have not been performed
in the geriatric population, geriatrics-specific problems are not expected to
limit the usefulness of this medication in the elderly. However, elderly
patients are more likely to have age-related renal function impairment, which
may require caution in patients receiving cyclophosphamide.
The bone marrow depressant effects of
cyclophosphamide may result in an increased incidence of microbial infection,
delayed healing, and gingival bleeding. Dental work, whenever possible should be
completed prior to initiation of therapy or deferred until blood counts have
returned to normal. Patients should be instructed in proper oral hygiene during
treatment, including caution in use of regular tooth brushes, dental floss, and
toothpicks. Cyclophosphamide may also rarely cause stomatitis associated with
considerable discomfort.
Because normal defense mechanisms may be
suppressed by cyclophosphamide therapy, concurrent use with a live virus vaccine
may potentiate the replication of the vaccine virus, may increase the
side/adverse effects of the vaccine virus, and/or may decrease the patient's
antibody response to the vaccine; immunization of these patients should be
undertaken only with extreme caution after careful review of the patient's
hematologic status and only with the knowledge and consent of the physician
managing the cyclophosphamide therapy. The interval between discontinuation of
medication that cause immunosuppression and restoration of the patient's ability
to respond to the vaccine depends on the intensity and type of immunosuppression-causing
medications used, the underlying disease, and other factors; estimates vary from
3 months to 1 year. Patients with leukemia in remission should not receive live
virus vaccine until at least 3 months after their last chemotherapy. In
addition, immunization with oral polio-virus vaccine should be postponed in
persons in close contact with the patient, especially family members.
Anorexia, nausea, and vomiting occur commonly
with cyclophosphamide, especially at high doses; some clinicians reported that
these effects respond to treatment with antiemetics. Occasionally, diarrhea,
hemorrhagic colitis, mucosal irritation, and oral ulceration have been reported.
Rarely, aphthous stomatitis, enterocolitis, and hepatotoxicity as evidenced by
jaundice and hepatic dysfunction have occurred.
Alopecia occurs frequently in patients who
receive cyclophosphamide and patients should be forewarned of this possibility.
In usual doses, about 33% of patients who receive the drug experience alopecia,
generally beginning about 3 weeks after initiation of therapy; the condition is
usually reversible but new hair may be a different color or texture. Transverse
ridging, retarded growth, and/or pigmentation of fingernails may occur, as well
as skin pigmentation. Nonspecific dermatitis has also been reported.
Other reported adverse effects of
cyclophosphamide include headache, dizziness, and myxedema. Faintness, facial
flushing, diaphoresis, and oropharyngeal sensation have occurred following IV
administration of cyclophosphamide, have been reported. The drug may interfere
with normal wound healing.
Some patients who have received
cyclophosphamide alone, as part of a combination regimen, or as adjunctive
therapy have developed secondary malignancies, most frequently urinary bladder,
myeloproliferative, & lymphoproliferative malignancies. Although a causal
relationship has not been definitely established, the possibility of development
of a secondary malignancy should be considered in weighing the possible benefit
from the drug against the potential risk. Secondary malignancies have occurred
most frequently in patients who have been treated with cyclophosphamide for
primary myeloproliferative & lymphoproliferative malignancies & primary
nonmalignant diseases in which immune processes are believed to be involved.
Secondary urinary bladder malignancies generally have occurred in patients who
previously developed hemorrhagic cystitis. In some cases, the secondary
malignancy was not detected until several years after discontinuance of
cyclophosphamide therapy. Long-term follow-up of women who received
cyclophosphamide-containing adjuvant chemotherapy regimens for the treatment of
early breast cancer indicates that the incidence of other solid tumors &
secondary leukemia in these women is not substantially greater than that in the
general population.
CAREFUL EVALUATION OF BONE MARROW FUNCTION IS
IMPERATIVE AND PROLONGED THERAPY IS GUIDED BY KEEPING THE TOTAL LEUKOCYTE COUNT
BETWEEN 2500 AND 4000 CELLS PER CUBIC MILLIMETER OF BLOOD OR BY OBTAINING THE
DESIRED RESPONSE OF THE TUMOR.
Potentially fatal cardiotoxicity also has
occurred when cyclophosphamide (given concomitantly with mesna /2-mercaptoethane
sulfonic acid sodium salt/ and followed with autologous bone marrow transplant)
was administered inadvertently in a dosage of 4 g/sq m daily for 4 doses rather
than in a total dose of 4 g/sq m administered over 4 days in equally divided
doses of 1 g/sq m daily as part of a phase I protocol.
One of the major and dose limiting adverse
effects of cyclophosphamide is hematologic toxicity, which is usually reversible
after discontinuance of the drug. Hematopoietic adverse effects include
leukopenia, thrombocytopenia, hypothrombinemia, and anemia. Leukopenia is
considered to be an expected effect of cyclophosphamide therapy and may be
severe. Leukopenia nadirs generally occur at 8-15 days following a single dose
of cyclophosphamide and recovery usually occurs within 17-28 days.
Thrombocytopenia is reportedly less common, with nadirs occurring 10-15 days
after administration of the drug. Anemia, particularly after large doses or
prolonged therapy, and rarely hypoprothrombinemia have been reported. Rarely,
cyclophosphamide has been reported to produce positive direct antiglobulin
(Coombs') test results and hemolytic anemia.
In children treated with cyclophosphamide a
transient blurring of vision has been reported in 5 out of 59, coming on in
minutes after intravenous injection in two and within 24 hours in the other
three. The duration of blurring ranged from one hour to two weeks, but vision
returned to normal in all.
Cyclophosphamide can cause sterility in people
of either sex. It can damage the germinal cells in prepubertal, pubertal and
adult males, and causes premature ovarian failure in females.
... To analyse the treatment-related
complications of busulphan and cyclophosphamide (BU-CY) as the conditioning
regimen for allogeneic peripheral blood stem cell transplantation (allo-PBSCT).
... The clinical data of 40 leukemia patients undergoing allo-PBSCT between June
1997 and May 1999 in our BMT center were retrospectively analysed. ... Recovery
of neutrophil and platelet was achieved at a median of day +13 (9 similar 28)
and day +12 (7 similar 60) respectively. Acute GVHD occurred in 17 of 40
patients (42.5%) with grade II-IV in 10 patients (25%). Chronic GVHD developed
in 21 out of 30 evaluable patients (70%). Mild to severe mucositis occurred in
30 patients (75%), and 4 of them had severe esophagitis with bleeding.
Haemorrhagic cystitis developed in 8/40 (20%) patients, the median time of its
onset was day +100 (+7 to +165). Six of 40 patients (15%) developed interstitial
pneumonia (IP), 5 of them were due to cytomegalovirus infection, and the
remaining one due to pneumocystis carinii infection. No hepatic veno-occlusive
disease was observed and no seizure occurred. During the median follow-up of 480
(300 similar 1000) days, 4 (10%) patients relapsed and 8 (20%) patients died of
the transplant-related complications. The 3 year leukemia-free survival rate was
70%. ... BU (domestic busulfan)-CY regimen is relatively easy to administer and
well tolerated, with low extramedullary toxicities.
... We now described five patients receiving
monthly cycles of iv CP /cyclophosphamide/ whose allergic reactions included
clinical features of type I hypersensitivity but were atypical in their markedly
delayed onset (i.e., 8 to 16 hr in patients 1 to 4 and 10 days in patient 5) ...
The objective was to investigate these late-developing clinical reactions by
skin testing with CP and two of its major metabolites ... The five patients and
a control group receiving iv CP uneventfully were studied by the same skin test
protocol ... The four individual in the control group were unreactive to CP or
its metabolites. All five patients with late-onset allergic reactions had
positive immediate skin test results to CP metabolites but not to CP itself. We
propose that the allergic reactions in patients 1 to 4 were mediated, wholly or
in major part, by IgE antibodies reactive with allergens derived from
time-dependent drug metabolites.
Sterile hemorrhagic cystitis has been reported
to occur in up to 20% of patients (especially children) on long-term
cyclophosphamide therapy. The effect, which rarely can be severe and even fatal,
is attributed to chemical irritation by active metabolites of cyclophosphamide
that accumulate in concentrated urine. Hematuria usually resolves spontaneously
within a few days after discontinuance of cyclophosphamide therapy but may
persist for several months. Fibrosis of the bladder (sometimes extensive), with
or without cystitis, also has occurred, but less frequently. Atypical epithelial
cells may be found in the urinary sediment. These adverse effects appear to be
related to the dosage and duration of cyclophosphamide therapy. Nephrotoxicity,
including hemorrhagic ureteritis and renal tubular necrosis, has been reported;
such lesions reportedly resolve in most instances following discontinuance of
cyclophosphamide therapy.
THERE HAVE BEEN AT LEAST 30 CASE REPORTS OF
MALIGNANCY IN PATIENTS TREATED WITH CYCLOPHOSPHAMIDE FOR NONMALIGNANT DISORDERS,
MAINLY RHEUMATOID ARTHRITIS AND CHRONIC GLOMERULONEPHRITIS. THESE INCLUDED 17
ACUTE NONLYMPHOCYTIC LEUKEMIAS, ONE CHRONIC NONLYMPHOCYTIC LEUKEMIA, ONE ACUTE
LYMPHOCYTIC LEUKEMIA, ONE CHRONIC LYMPHOCYTIC LEUKEMIA, TWO BLADDER CANCERS, ONE
SQUAMOUS CELL CANCER OF THE SKIN, THREE RETICULUM CELL SARCOMAS, ONE HODGKIN'S
DISEASE, ONE MELANOMA, TWO CEREBRAL GLIOMAS, ONE CERVICAL CANCER AND ONE PLEURAL
SARCOMA. /MONOHYDRATE/
Gonadal suppression, resulting in amenorrhea
or azoospermia, may occur in patients taking antineoplastic therapy, especially
with the alkylating agents. In general, these effects appear to be related to
dose & length of therapy & may be irreversible. Prediction of the degree
of testicular or ovarian function impairment is complicated by the common use of
combinations of several antineoplastics, which makes it difficult to assess the
effects of individual agents. However, there have been numerous reports of
gonadal suppression with use of cyclophosphamide, which seems to depend on dose,
duration, & state of gonadal function at the time of therapy, sterility may
be irreversible in some patients.
THERE WAS INCR IN NUMBER OF CHROMOSOMAL
ABERRATIONS IN THE PERIPHERAL BLOOD LYMPHOCYTES OF CHILDREN TREATED WITH
CYCLOPHOSPHAMIDE (3-5 MG/DAY FOR 6-8 MONTHS) FOR NONMALIGNANT CONDITIONS &
OF PATIENTS WITH RHEUMATOID ARTHRITIS FOLLOWING CYCLOPHOSPHAMIDE TREATMENT.
SIMILAR INCR WERE OBSERVED IN LYMPHOCYTES OF WOMEN WITH RECURRENT OVARIAN OR
UTERAL CARCINOMA 3 OR 24 HR AFTER AN IV ADMIN OF 2.0 G & IN THE BONE MARROW
& LYMPH NODE CELLS OF PATIENTS WITH LYMPHOGRANULOMATOSIS 24-72 HR AFTER
SINGLE DOSE OF 400 MG CYCLOPHOSPHAMIDE. INCR LEVELS OF SISTER CHROMATID EXCHANGE
IN PERIPHERAL BLOOD LYMPHOCYTES HAVE BEEN OBSERVED IN PATIENTS TREATED WITH
CYCLOPHOSPHAMIDE. THESE HAVE INCLUDED PATIENTS WITH MALIGNANT LYMPHOMA &
NEPHROTIC SYNDROME, A PATIENT WITH RETICULOSARCOMA, 3 PATIENTS WITH UNSPECIFIED
MALIGNANT TUMORS & 1 PATIENT WITH ACUTE GLOMERULONEPHRITIS. /MONOHYDRATE/
LEUKOPENIA IS INEVITABLE SIDE EFFECT & IS
USED AS INDEX OF DOSAGE ... HYPOPROTHROMBINEMIA ... .
Nausea & vomiting, myelosuppression with
platelet sparing, & alopecia are common to virtually all regimens using
cyclophosphamide. Mucosal ulcerations &, less frequently, interstitial
pulmonary fibrosis also may result from cyclophosphamide treatment.
Extravasation of the drug into subcutaneous tissues does not produce local
reactions, & thrombophlebitis does not complicate iv admin. The occurrence
of sterile hemorrhagic cystitis has been reported in 5%-10% of patients. As
noted above, this has been attributed to chemical irritation produced by
acrolein. Its incidence is significantly reduced by coadministration of mesna.
For routine clinical use, ample fluid intake is recommended. Admin of the drug
should be interrupted at the first indication of dysuria or hematuria. The
syndrome of inappropriate secretion of antidiuretic hormone (ADH) has been
observed in patients receiving cyclophosphamide, usually at doses higher then 50
mg/kg. It is important to be aware of the possibility of water intoxication,
since these patients usually are vigorously hydrated.
Medical Surveillance:
PRECAUTIONS FOR "CARCINOGENS":
Whenever medical surveillance is indicated, in particular when exposure to a
carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic
and/or other/ tests that might become useful or mandatory. /Chemical
Carcinogens/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There
is no method available for routine monitoring of personnel for evidence of
hazardous drug exposure. Tests for the presence of mutagens or chromosomal
damage are not drug specific and are of value only in controlled studies.
Chemical analysis of urine for the presence of hazardous drugs at the
sensitivity level needed to detect occupational exposure is limited to a few
drugs and is not yet commercially available. /Antineoplastic agents/
Probable Routes of Human Exposure:
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
danger to health-care personnel from handling a hazardous drug stems from a
combination of its inherent toxicity and the extent to which workers are exposed
to the drug in the course of carrying out their duties. This exposure may be
through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches),
inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic
agents/
NIOSH (NOES Survey 1981-1983) has
statistically estimated that 30,026 workers (20,745 of these are female) are
potentially exposed to cyclophosphamide in the US(1). Occupational exposure to
cyclophosphamide may occur through inhalation and dermal contact with this
compound at workplaces where cyclophosphamide is produced or used(SRC). Workers
involved in formulating and dispensing the drug may be exposed through dermal
contact (with the dry powder or solutions), or inhalation of dust(SRC). Direct
human exposure occurs through ingestion of the drug (when dispensed in tablet
form) and through injection (when administered intravenously)(2).
Air monitoring conducted in a West German
manufacturing facility in April 1984 found cyclophosphamide levels ranging from
0.1 to 810 ug/cu m(1). Air concentrations of 2-480 ug/cu m were detected in a
production area of a plant involved weighing cyclophosphamide and formulating it
into tablets(1). No detectable levels (detection limit of 0.05 ug/cu m) were
found in air samples (taken from flow hoods) from a hospital dispensing and
administering cyclophosphamide; however, filter media from the flow hoods
contained measurable quantities suggesting that some exposure can occur(1).
Concentrations of cyclophosphamide in personal air samplers from a manufacturing
facility ranged from less than the detection limit to 97.0 ug/cu m, and in a
laminar-flow hood, the concentrations ranged from 0-60 ng/cu m(2).
Body Burden:
In a cross-sectional study, the urine of 20
hospital workers occupationally exposed to cyclophosphamide and 21 unexposed
controls was monitored for excretion of cyclophosphamide. During the week in
which samples were collected, most of the workers handled cyclophosphamide fewer
than 5 times and the amount handled each time ranged from 100-1000 mg (mean +/-
350 mg). All workers claimed to have taken regular safety precautions, ie, at
least wearing gloves during handling. The drug was identified in 5 cases (range:
0.7-2.5 ug excreted/24 hr urine). A clear relationship between cyclophosphamide
handling and urinary detection was shown. 4 of 5 persons with detectable urinary
cyclophosphamide had handled cyclophosphamide 10 times or more during the week.
Cyclophosphamide (along with ifosfamide) was
detected in the urine of 8 pharmacy technicians and nurses (along with
ifosfamide) at amounts ranging from <0.001-0.5 ug(1). 21 nurses and pharmacy
personnel in a Munich, Germany hospital were monitored for compound exposure; on
days when 3,900 mg/l cyclophosphamide was mixed, 12 of 31 urine samples tested
positive with concentrations ranging from 3.5 to 38 ug/24 hr urine(2).
Antidote and Emergency Treatment:
Basic treatment: Establish a patent airway.
Suction if necessary. Watch for signs of respiratory insufficiency and assist
ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15
L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for
shock and treat if necessary ... . Anticipate seizures and treat if necessary
... . For eye contamination, flush eyes immediately with water. Irrigate each
eye continuously with normal saline during transport ... . Do not use emetics.
For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for
dilution if the patient can swallow, has a strong gag reflex, and does not drool
... . Cover skin burns with dry sterile dressings after decontamination ... .
/Poison A and B/
Advanced treatment: Consider orotracheal or
nasotracheal intubation for airway control in the patient who is unconscious,
has severe pulmonary edema, or is in respiratory arrest. Positive pressure
ventilation techniques with a bag valve mask device may be beneficial. Monitor
cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP:
"To keep open", minimal flow rate/. Use lactated Ringer's if signs of
hypovolemia are present. Watch for signs of fluid overload. Consider drug
therapy for pulmonary edema ... . For hypotension with signs of hypovolemia,
administer fluid cautiously. Watch for signs of fluid overload ... . Treat
seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist
eye irrigation ... . /Poison A and B/
Animal Toxicity Studies:
Evidence for Carcinogenicity:
Classification of carcinogenicity: 1) evidence
in humans: sufficient; 2) evidence in animals: sufficient. Overall summary
evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic
to humans. /From table/
The Carcinogen Assessment Group in EPA's
Research and Development Office has evaluated cyclophosphamide for
carcinogenicity. According to their analysis, the weight of evidence for
cyclophosphamide is group C, which is based on inadequate evidence in humans and
limited evidence in animals. As a group C chemical, cyclophosphamide is
considered a possible human carcinogen.
Non-Human Toxicity Excerpts:
TWO GROUPS OF 10 MALE AND 10 FEMALE, 4 TO 24
WEEK OLD NZB/NZW HYBRID MICE /WHICH DEVELOPED AUTOIMMUNE COMPLEX NEPHRITIS/ WERE
GIVEN DAILY SC INJECTIONS OF 1 MG/KG BODY WT OR 8 MG/KG BODY WT CYCLOPHOSPHAMIDE
IN 0.1 ML SALINE FOR UP TO 93 WK; 20 MALES AND 20 FEMALES WERE INJECTED WITH
SALINE ALONE AND SERVED AS CONTROLS. FIFTY PERCENT OF MALE CONTROLS HAD DIED BY
THE 31ST WK OF THE STUDY, COMPARED WITH 41 AND 60 WK FOR THOSE GIVEN THE LOW AND
HIGH DOSE LEVELS. FIFTY PERCENT OF MALE CONTROLS HAD DIED BY 57 WK, COMPARED
WITH 71 AND 80 WK FOR THE TREATED ANIMALS. TUMORS WERE OBSERVED IN TREATED MALES
AFTER 60 WK OF TREATMENT AND IN FEMALES AFTER 40 WEEKS. EIGHT MALES & 9
FEMALES GIVEN THE HIGHEST DOSE LEVEL DEVELOPED NEOPLASMS, INCL 3 GENERALIZED
LYMPHORETICULAR NEOPLASMS IN MALES AND 3 IN FEMALES AS WELL AS A POORLY
DIFFERENTIATED SARCOMA. 3 SQUAMOUS CELL CARCINOMAS OCCURRED AT THE SITE OF
INJECTION IN FEMALES. PULMONARY ADENOMAS WERE ALSO OBSERVED IN 3 MALE AND 1
FEMALE MICE. OF ANIMALS GIVEN THE LOW DOSE LEVEL, 3 MALES AND 1 FEMALE DEVELOPED
NEOPLASMS. AMONG CONTROLS 2 MALE AND 1 FEMALE MICE HAD RETICULUM CELL SARCOMAS.
/MONOHYDRATE/
A GROUP OF 50 FEMALE NMRI MICE, 65 DAYS OLD,
RECEIVED 52 WEEKLY SC INJECTIONS OF 26 MG/KG BODY WT (7% OF LD50)
CYCLOPHOSPHAMIDE (TOTAL DOSE, 1352 MG/KG BODY WT); ANOTHER GROUP OF 50 FEMALES
SERVED AS CONTROLS. THE AVERAGE LIFESPAN OF TREATED AND CONTROL ANIMALS WAS 630
+ OR - 130 DAYS. IN THE CONTROL GROUP, 3/46 (6%) MICE DEVELOPED STEM CELL
LEUKEMIA AND NO OTHER MALIGNANT TUMOR WAS OBSERVED. OF THE TREATED MICE, 28/46
(61%) DEVELOPED MALIGNANT TUMORS: 3 LEUKEMIAS, 12 MAMMARY CARCINOMAS & 1
OTHER MAMMARY TUMOR, 4 OVARIAN CARCINOMAS, 1 FIBROSARCOMA OF THE THORAX, 1 SKIN
CARCINOMA, 2 SARCOMAS @ INJECTION SITE & 4 LUNG TUMORS. /MONOHYDRATE/
FOUR GROUPS OF 15 MALE AND 15 FEMALE A/J MICE,
4-6 WK OLD, WERE GIVEN IP INJECTIONS OF CYCLOPHOSPHAMIDE IN WATER 3 TIMES A WK
FOR 4 WK (TOTAL DOSES, 420, 135, 34 AND 8 MG/KG BODY WT). OF 165 MALE AND 195
FEMALE CONTROLS INJECTED WITH WATER ONLY, 37% OF MALE AND 27% OF FEMALE
SURVIVORS DEVELOPED LUNG TUMORS WITHIN 39 WK, WITH 0.48 AND 0.29 TUMORS/MOUSE.
AFTER 39 WK, 4/30, 27/30, 26/30 AND 30/30 ANIMALS WERE STILL ALIVE IN THE
RESPECTIVE DOSE GROUPS. AMONG SURVIVING ANIMALS, THE NUMBERS WITH LUNG NEOPLASMS
WERE 2/4 (2.5 TUMORS/MOUSE), 20/27 (74%; 1.3 TUMORS/MOUSE), 11/26 (42%; 0.6
TUMORS/MOUSE) AND 12/30 (40%; 0.4 TUMOR/MOUSE, RESPECTIVELY. THE INCIDENCE OF
LUNG TUMORS IN TREATED MICE WAS SIGNIFICANTLY GREATER THAN THAT IN CONTROLS ONLY
FOR THOSE GIVEN THE SECOND HIGHEST DOSE LEVEL. /MONOHYDRATE/
A GROUP OF 29 DD MICE AND A GROUP OF 25 A MICE
OF BOTH SEXES, 4-5 WK OLD, RECEIVED IP INJECTIONS OF 5 MG/KG BODY WT
CYCLOPHOSPHAMIDE IN SALINE TWICE WEEKLY FOR 15 SUCCESSIVE WK; 20 AND 16 CONTROL
MICE OF EACH STRAIN WERE INJECTED WITH ISOTONIC SALINE ONLY. NEOPLASMS DEVELOPED
IN VARIOUS ORGANS IN 12/22 DD MICE THAT SURVIVED MORE THAN 48 WK AFTER THE
BEGINNING OF THE TREATMENT; THESE OCCURRED PREDOMINANTLY IN LUNG, LIVER, TESTIS
& MAMMARY GLAND. 3 OF 10 CONTROL DD MICE THAT LIVED BEYOND THE SAME PERIOD
ALSO HAD NEOPLASMS. NEOPLASMS DEVELOPED IN 6/16 STRAIN A MICE THAT SURVIVED MORE
THAN 42 WK AND INCLUDED 6 IN THE LUNG AND 1 IN THE ORBIT. TWO OF 11 CONTROL A
MICE HAD NEOPLASMS, BOTH IN THE LUNG. /MONOHYDRATE/
TWO GROUPS, EACH OF 25 MALE AND 25 FEMALE
OUTBRED SWISS-WEBSTER-DERIVED MICE, 6 WK OLD, WERE GIVEN IP INJECTIONS OF 12 OR
25 MG/KG BODY WT CYCLOPHOSPHAMIDE 3 TIMES A WK FOR 6 MO. ANIMALS THAT SURVIVED
OVER 100 DAYS WERE OBSERVED FOR UP TO 12 FURTHER MO, AT WHICH TIME THEY WERE
KILLED. LUNG NEOPLASMS OCCURRED IN 7/30 MALES COMBINED FROM BOTH TREATMENT
GROUPS AND IN 10/35 FEMALES; BLADDER PAPILLOMAS WERE FOUND IN 4/30 MALES. THE
INCIDENCES OF THE TWO TUMOR TYPES WERE REPORTED TO BE STATISTICALLY GREATER THAN
THOSE IN POOLED CONTROLS. THE WORKING GROUP CONSIDERED THAT THE INADEQUATE
REPORTING OF CERTAIN ITEMS, SUCH AS SURVIVAL TIMES, THE AMALGAMATION OF VARIOUS
EXPERIMENTAL GROUPS AND TUMOR TYPES, AS WELL AS THE LACK OF ADE-ADJUSTMENT IN
THE ANALYSES PRECLUDED A COMPLETE EVALUATION OF THIS STUDY. /MONOHYDRATE/
TWO GROUPS, EACH OF 25 MALE AND 25-28 FEMALE
CHARLES RIVER CD RATS, 6 WK OLD, WERE GIVEN IP INJECTIONS OF 5 OR 10 MG/KG BODY
WT CYCLOPHOSPHAMIDE 3 TIMES A WK FOR 6 MO. ANIMALS THAT SURVIVED OVER 100 DAYS
WERE OBSERVED FOR 12 FURTHER MO, AT WHICH TIME THEY WERE KILLED. MAMMARY
CARCINOMAS OCCURRED IN 9/53 FEMALES COMBINED FROM BOTH TREATMENT GROUPS AND IN
1/50 MALES, & MAMMARY ADENOMAS OCCURRED IN 24/53 FEMALES. THE INCIDENCE OF
ADENOCARCINOMAS IN CONTROL FEMALES WAS 13/181; THE INCIDENCES OF THE TWO MAMMARY
TUMOR TYPES WERE REPORTED TO BE INCR TO A STATISTICALLY SIGNIFICANT EXTENT OVER
THOSE IN POOLED FEMALE CONTROLS. THE WORKING GROUP CONSIDERED THAT THE
INADEQUATE REPORTING OF CERTAIN ITEMS, SUCH AS SURVIVAL TIMES, THE AMALGAMATION
OF VARIOUS EXPERIMENTAL GROUPS AND TUMOR TYPES, AS WELL AS THE LACK OF AGE
ADJUSTMENT IN THE ANALYSES PRECLUDED A COMPLETE EVALUATION OF THIS STUDY.
/MONOHYDRATE/
A GROUP OF 32 MALE SPRAGUE DAWLEY RATS, 3 MO
OLD RECEIVED WEEKLY IV INJECTIONS OF 13 MG/KG BODY WT CYCLOPHOSPHAMIDE (TOTAL
DOSE, 670 MG/KG BODY WT). A GROUP OF 52 UNTREATED RATS SERVED AS CONTROLS.
MALIGNANT TUMORS DEVELOPED IN 14/32 TREATED RATS WITHIN 510 + OR - 90 DAYS:
THERE WERE 3 RETICULUM CELL SARCOMAS, 6 HEMANGIOENDOTHELIOMAS IN VARIOUS ORGANS,
1 NEUROGENIC SARCOMA OF MEDIASTINUM, 1 SARCOMA OF THE HEART & 1 LEUKEMIA;
TWO RATS HAD 2 MALIGNANT TUMORS. EACH: ONE HAD OSTEOSARCOMA OF PARANASAL SINUS
& A PHEOCHROMOCYTOMA, AND THE OTHER HAD AN ANGIOSARCOMA OF THE ABDOMEN AND A
PHEOCHROMOCYTOMA. OF THE CONTROLS, 6/52 DEVELOPED MALIGNANT TUMORS WITHIN 670 +
OR - 150 DAYS: 3 RETICULUM CELL SARCOMAS, 1 PHEOCHROMOCYTOMA, 1 HEMANGIOSARCOMA
OF THE LUNG AND 1 SARCOMA OF THE KIDNEY. /MONOHYDRATE/
A SINGLE IP DOSE OF CYCLOPHOSPHAMIDE CAUSES
MARKED NECROSIS OF THE BLADDER AND OF THE TUBULAR AND PELVIC EPITHELIUM IN MICE,
RATS, & DOGS; RELATIVELY LITTLE DAMAGE WAS OBSERVED IN LIVER, EVEN AFTER
PROLONGED ADMINISTRATION. NECROSIS OF BLADDER TISSUE IS FOLLOWED BY RAPID
EPITHELIAL REGENERATION OF DIPLOID CELLS & LATER PRODUCTION OF TETRAPLOID,
OCTOPLOID & OCCASIONAL HYPERPLOID CELLS. /MONOHYDRATE/
CYCLOPHOSPHAMIDE IS TERATOGENIC IN SEVERAL
SPECIES, INCL MICE, RATS, RABBITS, & CHICKENS. IT PRODUCES A VARIETY OF
SKELETAL, SOFT TISSUE & OTHER MALFORMATIONS & INCR NUMBER OF RESORPTIONS;
THE TYPE AND FREQUENCY OF MALFORMATIONS ARE STRICTLY DOSE & TIME DEPENDENT.
/MONOHYDRATE/
CYCLOPHOSPHAMIDE IS ALSO TERATOGENIC IN THE
RHESUS MONKEY WHEN GIVEN INTRAMUSCULARLY FOR VARIOUS PERIODS BETWEEN DAYS 25 AND
43 OF PREGNANCY AT DOSES RANGING BETWEEN 2.5 AND 20 MG/KG BODY WT. THE INDUCED
ABNORMALITIES INCLUDED CLEFT LIP WITH CLEFT PALATE, EXOPHTHALMUS, A MARKED
UNDERDEVELOPMENT OF THE MIDFACIAL BONES AND MENINGOENCEPHALOCELE. /MONOHYDRATE/
Teratogenic effects were induced in outbred
mice by treatment of 8 wk old pregnant females with 1 of 5 different doses (5,
10, 20, 30, & 40 mg/kg, ip) of cyclophosphamide. Most malformations were
induced with 20, 30, or 40 mg/kg, whereas 5 & 10 mg of cyclophosphamide/kg
caused no alterations of the fetuses.
TEN PREGNANT FEMALE RABBITS WERE TREATED WITH
A DAILY INJECTION OF 50 MG CYCLOPHOSPHAMIDE (DNA SYNTHESIS INHIBITOR), FROM DAY
11 TO DAY 14, WHICH IS A PERIOD THAT PRECEDES FORMATION OF THE FACE. THE CONTROL
SAMPLE COMPRISED FIVE FEMALE RABBITS. THE FETUSES WERE OBTAINED BY CESAREAN
SECTION ON DAY 28 & STAINED WITH ALIZARIN. SIX OF THE TEN TREATED ANIMALS
PRODUCED OFFSPRING THAT HAD TEMPOROMANDIBULAR JOINT SYNOTOSIS (TMJ).
Pregnant CBA/CA mice were injected
subcutaneously with 0, 4, 20, or 40 mg/kg of cyclophosphamide 60 hr after
copulation. At each of the doses tested, cyclophosphamide significantly reduced
the number of blastocyst cells and caused dose related increase in chromosome
aberrations in the blastocysts. Cyclophoshamide increased the number of cells
with chromosome breaks at all three doses and also increased chromosome
rearrangements in the 20 and 40 mg/kg treated groups. The number of cells with
ring chromosomes in the 40 mg/kg group was significantly increased.
Cyclophosphamide inhibited the synthesis of DNA and of histones in the 20 and 40
mg/kg groups. On a subsequent culture study, it was observed that treatment of
the mothers with 20 or 40 mg/kg, significantly inhibited the in vitro hatching
of blastocysts from the zona pellucida. Trophoblast expansion and the attachment
of embryos to the glass coverslip were also inhibited.
Five groups of C57BL/6J pregnant mice were
treated as follows: 1) 1 ug/g daily iv of saline or cyclophosphamide on day 9-12
or 14-17 of gestation (vehicle and drug were given by injection into the tail
vein); 2) 5 ug/g iv vehicle or cyclophosphamide on day 12 of gestation; 3) 1,
2.5, or 5 ug/g ip vehicle or cyclophosphamide on day 12 of gestation; 4) 5, 10,
or 20 ug/g ip vehicle or cyclophosphamide on day 17 of gestation; and 5) 10 or
20 ug/g ip vehicle or cyclophosphamide on day 17 of gestation. Number of
offspring per female at weaning was similar in controls and all groups except
for group 2 in which no offspring of treated dams survived. No gross terata were
present. No effect on cell mediated or immune function was observed in
offsprings of treated dams. The 5 and 9 week old progeny exposed to 20 ug/g on
gestational day 17 had reduced body weight. Decreased numbers of antibody
forming cells per spleen were found in 8 week old offspring in group 3.
CYCLOPHOSPHAMIDE ... HAS BEEN TESTED BY
INJECTION INTO THE ANTERIOR CHAMBER OF RABBIT EYES, BUT PROVED EXCESSIVELY
DAMAGING TO THE CORNEA TO ALLOW ITS USE IN TREATMENT OF EPITHELIAL INVASION OF
THE ANTERIOR CHAMBER. HOWEVER, INJECTIONS INTO THE VITREOUS BODY IN RABBITS IN
CONCENTRATIONS UP TO 10 MG/ML HAVE BEEN TOLERATED WITHOUT EXCESSIVE INFLAMMATION
... .
Cyclophosphamide & two of its metabolites,
4-hydroxycyclophosphamide & phosphoramide mustard were analyzed for their
ability to induce sister chromatid exchanges in mouse peripheral blood
lymphocytes in vitro & in vivo. In the in vivo experiments each animal
received a single ip injection of the cmpd in question at varying doses. In the
first experiment on phosphoramide mustard effects, the SCEs/metaphase was 16.04
at a dose of 19.0 uM/kg, the only result significantly different from the
control (13.24). In a second experiment, exposure to 50 uM/kg of either
cyclophosphamide or phosphoramide mustard induced sister chromatid exchange
frequencies of 28.06 & 21.81, compared with the control, 12.02. In the third
experiment, both phosphoramide mustard & 4-hydroxycyclophosphamide induced
dose dependent incr in sister chromatid exchange frequency (max, about 30 at 150
uM/kg for each cmpd compared with the control of about 10). At equimolar concns
of 1 uM, the mean sister chromatid exchange frequency was about 10 for the
control & cyclophosphamide, about 21 for phosphoramide mustard, & about
26 for 4-hydroxycyclophosphamide. The in vitro exposures used mononuclear
lymphocytes isolated from whole blood pooled from 18 male mice. Lymphocytes were
then inoculated into 1 ml of culture media containing 1 uM of either
cyclophosphamide phosphoramide mustard, or 4-hydroxycyclophosphamide &
incubated for 21 hr. The cells were then washed & the medium replenished,
this time without mitogen but containing 5 uM 5-bromo-2'-deoxyuridine.
The carcinogenic agent cyclophosphamide was sc
admin at 0 (controls), 13, and 26 mg/kg for life to groups of 30 female AKR
mice, and to groups of 30 NMRI mice. No symptoms of acute or subacute toxicity
were observed. CPA dose-dependently incr the median life span in AKR mice by 27%
at 13 mg/kg (from 188 to 238 days) and 76% at mg/kg (to 330 days), and decr the
incidence in leukemias by 17% and 37%. In NMRI mice, cyclophosphamide
significantly increased the incidence of leukemias by 46% at the low dose and
26% at the high dose, respectively. The number of benign and malignant tumors
for the high, low, and control groups were 16, 19, and 4 an 3 for NMRI mice. For
AKR mice, the tumor numbers were 22, 27, and 30, respectively. Histologically,
malignant tumors of the lymphoproliferative system were found to be lyphocytic
leukemias (98%) and the malignant thymomas (2%).
Virtually all nonobese diabetic/WEHI mice
spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis),
but very few progress to diabetes ( < 10% in females and < 1% in males at
220 days of age). Cyclophosphamide was admin to non-obese diabetic/WEHI mice at
0, 50, 100, 150, 200, or 300 mg/kg ip in 200 ul phosphate-buffered saline.
Diabetes was produced in both sexes 10 to 16 days after admin. There were no
significant changes in body wt, and the mortality was < 5% within 28 days.
Diabetes incidence decr with decr doses of cyclophosphamide and with < 100
mg/kg, there is no incr in incidence over controls. Cells in the insulitis
lesion were mainly T-lymphocytes with an initial preponderance of L3T4 cells.
Cyclophosphamide dramatically depleted splenic cell numbers from a baseline of
(1.2 + or - 0.4) x 10+8 to (1.4 + or - 0.5) x 10+7 by day 4. In expt 2, 3 mice
of each sex from the strains Biozzi, BALB/c, BALB/c nude, C3H/He, C3H/HeJ,
C57BL/6, C57/Bg, C57 nude, DBA/2, CBA/Ca and CBA nude were injected twice at a
14 day interval with 300 mg/kg ip cyclophosphamide. Non-obese diabetic/WEHI mice
(19 female and 15 male) received the same treatment and served as controls. No
mice were hyperglycemic 14 days after the second dose, except for the non-obese
diabetic mice (13 females and 8 males. Normal islets were found in all non-obese
diabetic mice. In exp 3, male non-obese diabetic/WEHI mice were given either an
organcultured fetal pancreas isograft, or cyclophosphamide followed 3 days later
with a pancreas isograft. Beta cell damage and insulitis in the host pancreas
were paralleled in the fetal pancreas isograft. Admin of cyclophosphamide to
mice 3 days before grafting caused greater graft infiltration and beta cell
loss, and in some cases, no beta-cells were present in the graft. In exp 4, 20
normoglycemic female non-obese diabetic/WEHI mice received a 300 mg/kg ip dose
of cyclophosphamide and then either given: (1) (n= 12) iv injections at 8, 24,
48, 96, and 168 hr, with 300 uL of mononuclear cell suspension from female
non-obese diabetic/WEHI mice; (2) (n= 12) also injected with phosphate-buffered
saline/FCS at the same time; (3) (n= 4) injections with cells obtained from
acutely diabetic non-obese diabetic mice. The transfer of lymph node and spleen
mononuclear cells to non-obese diabetic mice given cyclophosphamide prevented
diabetes. The transfer of sufficient lymphoid cells from young (nondiabetic)
mice prevented the
To investigate the early ovarian changes after
cyclophosphamide treatment, immature rats primed for 48 hr with pregnant mare
serum gonadotropin were given injections ip of cyclophosphamide (100 mg/kg) at
1, 2, 4, 16, and 24 hr before decapitation. Serum estradiol dropped
significantly after 24 hr of exposure to cyclophosphamide (p< 0.001).
Following 16 and 24 hr of cyclophosphamide exposure, the number of granulosa
cells expressed from each ovary decr (p< 0.05 and p< 0.01, respectively);
the number of nucleated bone marrow cells decr (p< 0.01 and p< 0.01), and
their median nuclear size was significantly reduced (p< 0.05 and p< 0.05)
as measured by Coulter Counter and C-256 channelyzer; and the mean follicular
diameter and the number of follicles with diameters > 300 uM were
significantly lower than in control. After 4, 16, and 24 hr of exposure, median
granulosa cell nuclear size significantly incr (p < 0.05, p < 0.01, and p
< 0.01, respectively), DNA cross-link in granulosa cells, measured by
alkaline elution, reached a max at 2 hr of exposure and decr thereafter.
Swiss Webster mice treated orally with
cyclophosphamide (1, 2.5 or 5 mg/kg) once daily on gestational days 6 through 18
gave birth to pups which appeared to be normal and the majority of which
survived to adulthood. There were no overt signs of maternal toxicity or any
changes in maternal body wt gains. Treatment caused a reduction of mean pup
weight at birth (1.5 at 5 mg/kg cyclophosphamide vs 1.8 for controls, and an
incr in cumulative pup mortality (32/151 at 5 mg/kg cyclophosphamide vs 5/76 for
controls). However, pregnancy outcome and mean pup body, spleen, and thymus
weights, when measured at 4 weeks of age, were within the control ranges.
Hematological profiles, serum immunoglobulin (IgG, IgM) levels and histology of
lymphoid tissue (spleen and thymus), assessed at 4 weeks of age, were not
affected by the maternal treatment. Treatment with 7.5 mg/kg Cyclophosphamide
not only resulted in reduced litter size (5.6 + or - 1.0 vs 12.6 + or - 0.3, but
also increased the cumulative pup mortality (71/68 vs 5/76 for controls). With
7.5 mg/kg cyclophosphamide, histopathological changes were observed in the
thymus in 2 and 3 week old pups. The morphology of the thymus in 4 week old pups
was unremarkable. At the dose of 10 mg/kg, no live births were recorded.
Treatment with 7.5 or 10 mg/kg cyclophosphamide resulted in significant
reduction in the maternal wt gain, compared with controls.
The cytostatic agent cyclophosphamide (1X10-5,
10-7 and 10-9 mg/ml) was tested in the initiator tRNA acceptance assay for
carcinogens in the presence of 2 concn of microsomal enzymes and NADPH.
Treatment of tRNA resulted in a 75% inhibition of its acceptance of L-methionine.
Cyclophosphamide also inhibited the charging of unfractionated tRNA from rat
liver with L-alanine, L-lysine, L-phenylalanine and L-valine.
Studies in animals have shown that
cyclophosphamide is teratogenic in mice, rats, rabbits, and monkeys given 0.02,
0.08, 0.5, and 0.07 times the human dose, respectively.
7 to 10 mg/kg were administered to rats and
with treatment on the 11th or 12th day the fetuses developed skeletal defects,
cleft palates and exencephaly or encephalocele. This compound was shown to be
relatively more embryolethal than chloroambucil when the fetal-maternal toxicity
ratios of the two were compared. The compound was found to be teratogenic in
mice. In the rabbit, a high incidence of cleft lip and-or palate and reduction
defects of the extremities using intravenously 30 mg/kg on single days 11, 12 or
13 was found. In the rhesus monkey, 10 mg/kg on days 27 through 29 produced
facial clefts and when given on days 32 through 40, meningoencephalocele was
observed.
A number of studies of the metabolism of
cyclophosphamide & its products in in vitro cultures with rat embryos have
shown that the cmpd must be bioactivated by a liver monofunctional oxygenase
system in order to be teratogenic. The morphologic changes found in vitro were
very similar to those seen in vivo. Phosphoramide mustard in equimolar doses
caused effects similar to those of bioactivated cyclophosphamide in vitro &
when given intraamnioticaly. Acrolein was toxic but its effect was difficult to
assess because of protein binding. The other stable metabolite,
4-ketocyclophosphoramide, was only weakly teratogenic in vitro. /It was/
concluded that phosphoramide mustard was the active teratogenic metabolite in a
mouse blastocyst system. The monofunctional form of phosphoramide mustard (with
only one chloroethyl side chain) has been shown to have
the same embryotoxicity as cyclophosphamide.
1.4, 3.4 or 5.1 mg/kg were administered daily
before mating to male rats. On the day of mating the males were not treated.
Minimal changes in the male reproductive tract were found but malformations and
retardation of growth were found in the offspring of the untreated females they
bred with. There was a dose-dependent increase in resorptions and fetal deaths.
In the offspring of males treated at 7-9 weeks there were 4 defects in 57
compared to one in 254 of the controls. The defects were hydrocephalus,
micrognathia and edema. Growth retardation occurred in 7% of the fetuses in this
group.
When used clinically, the important side
effects of cyclophosphamide are bone marrow suppression, with both leukopenia
& thrombocytopenia. Nausea & vomiting are rare. Sterile necrotizing
hemorrhagic cystitis has been associated with chronic admin & is a cause for
stopping therapy. To decr the incidence of this cystitis, which is manifested by
bloody urine, the drug should be administered in the morning & animals
should be encouraged to urinate frequently. Alopecia occurs occasionally in dogs
with continuous hair growth (eg, Poodles, Old English Sheepdogs).
Treatment of male rats with low dosages of
cyclophosphamide causes a dramatic incr in early embryo death among their
progeny without significantly affecting the general health of the male. It is
hypothesized that cyclophosphamide exerts its effects by targeting specific
components of spermatozoal nuclei. The purpose of the present studies was to
investigate the effects of chronic cyclophosphamide treatment on spermatozoal
DNA. Two approaches were pursued. The first was to determine total DNA damage by
using the alkaline elution method. The second was to study spermatozoal DNA
template function by using an in vitro DNA synthesis system. Adult male rats
were treated with saline or cyclophosphamide (6.1 mg/kg/day) daily for 1 or 6
wk. Cauda epididymal spermatozoa were collected & subjected to alkaline
elution using DNA-DNA dot hybridization to quantify the fractionated DNA. One
week of treatment with cyclophosphamide caused DNA single strand breaks that
could be detected only in the presence of proteinase K in the lysis soln; no DNA
cross-links were observed in the animals that received l-wk drug treatment. In
contrast, 6 wk of treatment with cyclophosphamide induced a significant incr in
both DNA single strand breaks & cross-links in spermatozoal nuclei; the
cross-links were attributable primarily to DNA-DNA linkages. The availability of
spermatozoal DNA for template function was not affected by 1 wk of treatment
with cyclophosphamide but was markedly affected after 6 wk of treatment with
this drug. It is proposed that during chromatin transition processes the male
genome may be in an open dynamic state with many exposed sites that are
vulnerable to alkylating agents. Since there is no DNA repair during
spermiogenesis, damage to the genome by alkylation at this stage may be
cumulative, resulting in the production of dysfunctional germ cells.
Exposure of the male germ cell to
cyclophosphamide during spermatogenesis and sperm maturation can interfere with
development of the embryo. When male rats were treated with a chronic low dose
of cyclophosphamide for 4 wk there was a dramatic increase in early
postimplantation loss in their progeny, characterized by implantation sites
selectively lacking in embryonic tissues. The present study was designed t
determine the earliest appearance of a paternal effect of cyclophosphamide
treatment and to examine whether the embryonic lineage was selectively affected.
Male Sprague-Dawley rats were orally dosed for 4-5 wk with saline or 6 mg/kg per
day of cyclophosphamide; their progeny were obtained on Days 2, 2.5, 3, 4, and
4.5 of gestation. Paternal cyclophosphamide treatment had no effect on the mean
number of embryos per pregnant female. However, as early as Day 3 of gestation,
there was a significant decrease in cell number among the embryos sired by
cyclophosphamide-treated males, increasing to a greater than 50% decrease in
cell number by Day 4. The cell doubling time in embryos sired by treated males
(16 hr) was longer than that of controls (12 hr). This decreased proliferation
rate was confirmed by a dramatic decrease in the capacity of both Day 3 and Day
4 embryos sired by cyclophosphamide-treated males to incorporate (3)H-thymidine
over a 26-hr culture period. Cytogenetic analysis in a limited number of
blastomeres entering metaphase revealed no evidence of chromosomal
abnormalities. Both the trophectoderm and the inner cell mass cells were
proportionally decreased in Day 4.5 embryos sired by cyclophosphamide-treated
males. Thus, paternal cyclophosphamide exposure affected both cell lineages in
the conceptus as early as Day 3 of gestation.
A study of cyclophosphamide (CP)-induced DNA
damage and repair occurring in vivo was conducted in the brown Norway rat
myelocytic leukemia (BNML) model. DNA single-strand breaks (SSB), DNA-DNA
interstrand cross-links (DIC), DNA-protein cross-links (DPC), and DNA
double-strand breaks (DSB) were measured by alkaline and neutral elution. After
ip injection of 50 ng/kg CP, DIC were detectable at 1 hr and peaked at 8 hr. DPC
were detectable at 2 hr and peaked at 6 hr. Both DIC and DPC persisted at a
relatively high level until 28 hr. Dose-response curves for both DIC and DPC
were determined at 4 hr after CP injection over the dose range of 25-150 mg/kg.
These doses ranged from the minimally effective dose to doses curative for rats
bearing this leukemia (1- to 9-log kill of leukemia cells). No SSB or DSB was
observed at 4 hr after CP injection over the dose range of 15-250 mg/kg, but a
low level of SSB was observed at 18-28 hr after CP treatment. These data suggest
that the cytotoxic effect of CP in vivo is mediated mostly by DIC and DPC. SSB
appearing late after CP injection in vivo may be a reflection of repair of DIC
and DPC and an indication of the optimal timing for administration of DNA-repair
inhibitors. This observation is of interest since our earlier work demonstrated
that hydroxyurea can potentiate the therapeutic benefit of CP in this model when
it is given over the 4-day period immediately after CP treatment.
Strain differences in cytochrome P450 (P450)
expression were investigated in Sprague-Dawley (SDs) compared with Fischer 344s
(F344s) rats after admin of cyclophosphamide (CPA). Animals received a single
dose of CPA with sacrifice occurring 6 days post-treatment. At 130 mg/kg, male
F344s displayed a greater sensitivity to CPA, as evidenced by a 68% loss of
total hepatic microsomal P450 compared with only 35% in SDs. The most dramatic
change in P450 was the loss of 2C11 (84% in F344s, 52% in SDs). In the SD,
individual rat 2C11 activity was correlated (r sq=0.76), with the level of
plasma thyroxine in that animal. In male F344s admin CPA at 50 mg/kg, 43 &
44% losses in 2C11 activity (P<0.05) & thyroxine (P<0.01),
respectively, were observed, whereas activities characteristic of P450s 2C11,
3A2, 2A2, 2C6 & 2E1/1A2 were unaffected in SDs at this dose. CPA also
produced suppression of P450 in female SDs, including female-specific 2C12.
Correlation was observed between the loss of P450 expression & change in
body weight after treatment in both male & female animals, suggesting that
CPA downregulated P450 expression secondary to decr caloric intake. The
anorectic effect of CPA is believed to result from potent CNS stimulation,
accompanied by a state of adaptive hypothyroidism.
CP /cyclophosphamide/ decreased the activity
of the female rat hepatic enzymes 2A1, 2C6 &/or 2C12 & 2E1, NADPH-P450
oxidoreductase & 17 beta-oxidoreductase & the pulmonary enzyme 2B, 7
days after its admin. The decr in the activity of the enzymes 2E1 &
NADPH-P450 oxidoreductase were accompanied by a corresponding change in the amt
of enzyme protein indicating that the alteration in expression of these enzymes
occurred via changes in transcription &/or translation or protein
degradation ... CP also impaired its own activation 7 days after its admin to
the female rat ... The change in female enzyme profile was accompanied by a
reduction in the hormones oestradiol, T4 & T3 7 days after CP admin ...
Despite an apparent trend for an incr in activity on day 5, a decr on day 8
& a subsequent incr on day 11, repeat doses of CP to the male rat generally
did not alter the P450 isoforms 2A2, 2B1, 2C11, 2E1 & 3A2 or 17 beta-oxidoreductase,
NADPH-P450 oxidoreductase & steroid 5 alpha-reductase ... Chronic admin of
CP to the male rat significantly reduced erythromycin demethylase &
NADPh-P450 oxidoreductase 8 days following commencement of dosing &
significantly incr statistically significant incr in pulmonary 2B 5 days
following commencement of dosing ... Plasma testosterone & TSH were
unchanged following repeated dosing with CP while T3 was significantly decr on
days 5, 8 & 11 & T4 was significantly decr on day 8.
Paracoccidioidomycosis is an endemic fungal
disease widely distributed throughout Latin America. The potent immunosuppressor
cyclophosphamide (CY) has been used to modulate host immune response to
Paracoccidioides brasiliensis in an experimental model. Inbred male Buffalo/Sim
rats weighing 250-300 g were inoculated with 5X10+6 P. brasiliensis cells of the
yeast phase form by intracardiac route. One group of animals was treated with 20
mg/kg body weight at days +4, +5, +6, +7, +ll and +l2 post-infection, while a
control group was infected alone. No mortality was recorded in either group.
Treated rats presented: a) a decrease in granuloma size, which contained less
fungal cells; b) a lack of specific antibodies up to 35 days post-infection, and
c) a significant increase in the footpad swelling test (DTH) against
paracoccidioidin. Splenic cell transfer from CY-treated P. brasiliensis-infected
donors to recipients infected alone led to a significant increase in DTH
response in the latter versus untreated infected controls. Likewise, in treated
infected recipients transferred with untreated infected donor spleen cells,
footpad swelling proved greater than in controls. Thus, it would seen that each
successive suppressor T lymphocyte subset belonging to the respective cascade
may be sensitive to repeated CY doses administered up to 12 days post-infection.
Alternatively, such CY schedule may induce the appearance of a T cell population
capable of amplifying DTH response.
Liver microsomes were obtained from male
Hooded Wistar rats admin a single dose (ip) of saline or cyclophosphamide (200
mg/kg). Rats receiving cyclophosphamide (CP) were killed 1, 4, 7, 10 or 14 days
after CP admin. The O-demethylation of dextromethorphan to dextrorphan was used
to monitor 2D1 activity ... The mean Vmax for dextrorphan formation was reduced
significantly (p < 0.0001) 7, 10 and 14 days after CP admin compared with the
control group (control, 0.32 + or - 0.07; 7-day, 0.20 + or - 0.08; 10-day, 0.11
+ or - 0.02; and 14-day group, 0.15 + or - 0.02 nmol/mg/min) ... Western
blotting revealed that there was a significant reduction (p < 0.0005) in the
microsomal relative 2D1 content 10 days after CP admin compared with the control
group (control, 1.25 + or - 0.44; and 10-day group, 0.65 + or - 0.14) ... The
activity of reduced nicotinamide adenine dinucleotide phosphate P450 reductase
was significantly reduced (p < 0.0001) 7, 10 and 14 days following CP admin
(control, 215 + or - 24; 7-day, 102 + or - 20; 10-day, 59 + or - 4 and 14-day
group, 76 + or - 8 nmol/mg/min). Cytochrome b5 content was significantly reduced
(p < 0.0001) 7 and 10 days following CP admin (control, 0.46 + or - 0.13;
7-day, 0.28 + or - 0.07 and 10-day group, 0.20 + or - 0.03 nmol/mg) ... The
significant reductions in the activity or rat hepatic microsomal 2D1 following
CP admin, as seen by the alterations in mean Vmax for dextrorphan formation, do
not appear to be due to a single factor, but may result from a combo of several
events, incl reductions in relative 2D1 content, reduced nicotinamide adenine
dinucleotide phosphate P450-reductase activity and cytochrome b5 content.
The testicular toxicity of cyclophosphamide
(Cp) in rats was evaluated by quantitative morphometry of spermatogenic cycle
stages. Nine-week-old male Sprague-Dawley rats in Group 1 were given a single
oral administration of 100 mg/kg of Cp, and were sacrificed at 1, 7, 14 and 21
days thereafter. Rats in Group 2 were orally given 100 mg/kg/day of Cp for 2
days, followed by 50 mg/kg/day for the next 3 days, and were sacrificed at 1 and
4 days after the last administration. The numbers of seminiferous epithelia were
counted in the seminiferous tubules of stages II, V, VII and XII of the
spermatogenic cycle. The data were expressed as numbers of spermatogenic cells
per Sertoli cells per seminiferous tubule cross section. Animals in Group 1
showed decreased preleptotene spermatocytes at Day 7, decreased zygotene
spermatocytes at Day 14, and decreased pachytene spermatocytes at Day 21. In
group 2, testicular toxicity could also be clearly detected by this morphometric
approach. The present morphometric study thus indicates that testicular toxicity
can be detected from Day 7 even after a single administration of Cp.
As a first step in developing a potentially
more sensitive assay, micronucleus induction by cyclophosphamide (CP) was
assessed in an in vivo/in vitro system using rat bone marrow and spleen cells.
In each of two independent experiments, two rats/dose were treated i.p. with 0,
20, or 40 mg CP/kg and killed 6 hr later. Cultures were then established in the
presence of growth stimulants (interleukin-3 and granulocyte-macrophage colony
stimulating factor for bone marrow; lipopolysaccharide and concanavalin A for
spleen) and cytochalasin B, a cytokinesis inhibitor. Bone marrow cells were
harvested and slides prepared 24 hr after initiation, while spleen cells were
harvested at 48 hr. One thousand cells/tissue/group were scored for cell cycle
kinetics and 1000 binucleate (BN) cells were scored for micronuclei. In
addition, spleen cells were concurrently assayed for chromosome aberrations. A
dose-related cell cycle delay was observed in both tissues in both experiments.
Bone marrow showed a 6% average background frequency of micronucleated BN cells,
while the low dose induced an average of 20%, and the high dose 31%. For spleen,
the average control frequency of micronucleated BN cells was 3%, the low dose
induced a 40% average frequency, and the high dose 65%. Also in splenocytes, a
dose-dependent incr in chromosome aberrations was observed, with an almost
40-fold incr observed over the control value at the high dose.
Cyclophosphamide is a cyclic phosphamide
derivative of mechlorethamine that requires metabolic activation by the
cytochrome p450 oxidation system in the liver. Cyclophosphamide is given PO or
IV, and dose limiting leukopenia associated with bone marrow suppression is the
primary toxicity. Sterile hemorrhagic cystitis caused by acrolein, a metabolite
of cyclophosphamide, can occur and should be treated by active diuresis and
intravesicular administration of N-acetyleysteine. Mesna, a drug that acts to
detoxify metabolites of cyclophosphamide, has been used in human medicine to
preclude hemorrhagic cystitis.
Alkylating agents are cytotoxic and kill
rapidly dividing neoplastic and normal cells and have drastic effects on cells
of the immune system. For example, CY at high doses (300 mg/kg) can deplete mice
of their T and B lymphocytes ... . At lower doses (50-100 mg/kg), CY transiently
depletes B but not T cells in mice ... . Compensatory responses result in twice
the normal number of lymphocyte in spleens of mice 12-15 days following
treatment, whereas normal numbers return by day 30. CY can also reduce
macrophage and NK numbers and function ... . /Alkylating agents/
There is a need for a rapid assay to identify
agents that damage mitochondria because the mitochondrion may be an important
target for numerous environmental mitotoxins. Certainly at least one
chemotherapeutic regimen (CHOP therapy) that includes doxorubicin can induce
cardiomyopathy through mitochondrial genotoxicity in cardiac muscle cells. Yeast
cells (1.5 x 10(6)-10(7)) in water are spread on a YEPD plate, and, when the
suspension of cells has dried, a small well (12 mm diameter) is cut into the
agar; 200-400 microl of a solution of the presumptive mitochondrial genotoxin is
placed in the well, and the plates are incubated for 2 days. The genotoxin forms
a concentration gradient through the agar and affects the growing cells. An
overlay containing tetrazolium chloride is added, and the plates are incubated
for 6-24 hr. Respiring cells turn red, and nonrespiring cells, with damaged DNA
or inhibited respiratory chains, that are adjacent to the well, are white. A
white ring, or a more lightly colored red ring, around the well indicates the
presence of cells with lowered respiratory activity which may be fully
reversible when the mitochondrial genotoxin is removed. In preliminary
experiments, doxorubicin (= adriamycin) shows strong activity with this assay;
cyclophosphamide is negative, and 4-hydroxycyclophosphamide, a metabolite of
cyclophosphamide, is weakly positive. Ethidium bromide, methotrexate,
5-fluorouracil, and 5-fluorocytosine also are mitochondrial genotoxins.
Antifungal agents similar to 5-fluorocytosine and anthelmintic compounds such as
pyrvinium iodide can be powerful mitochondrial genotoxins.
In a previous study, we showed that soluble
low-molecular-mass tumor-associated antigens (sTAA) promote the anti-tumor
effect of the anticancer drug cyclophosphamide (CPA) on rat mammary
carcinogenesis. In this report, we analyzed the underlaying mechanisms. Studies
were performed on the spleen and lymph nodes from the following groups of
mammary tumor-bearing rats: i) control rats, ii) rats treated with sTAA, iii)
rats treated with CPA, iv) rats treated with CPA and sTAA. Different zones of
the spleen and lymph nodes were measured and their T cell content (CD4+ and CD8+
cells) was analyzed immunohistochemically. CPA decreased the size and cell
content of follicles, splenic areas related to the production of B cells, of the
marginal zone and to a lesser extent of the periarterial lymph sheath, and
decreased the number of CD4+ and, at a lower rate, of CD8+ T cells in the
spleen. Addition of sTAA restored activity in the splenic zones producing these
cells. Similar effects of CPA and sTAA were found in lymph nodes with
accumulation of B lymphocytes in the primary and secondary follicles and of T
lymphocytes, including both CD4+ and CD8+ cells, in the paracortical zone. We
suggest that inhibition of the functional activity of the immune system is one
of the main reasons for the toxic effects of chemotherapeutic drugs such as CPA
and that the tumor-suppressive antitoxic effects of sTAA result from their
activation of B- and T-lymphocyte production in this system, particularly in the
spleen and lymph nodes.
Trypanosoma cruzi-infected juvenile rats
develop severe cardiac sympathetic denervation in parallel with acute
myocarditis. This aspect has not been studied in adult rats, thought to be
resistant to this infection. The mechanism involved in T. cruzi-induced neuronal
damage remains to be completely elucidated. In juvenile rats, the mortality
during the acute phase depends on T. cruzi populations, ranging from 30% to
100%. Therefore, studies of mechanisms through hazardous procedures such as
immunosuppression are restricted. The current paper shows that adult rats
infected with T. cruzi (Y strain) develop severe acute myocarditis and cardiac
sympathetic denervation, despite null mortality and virtual absence of patent
parasitaemia followed by negative haemoculture. Recovery from the myocarditis
and denervation occurred but PCR studies showed persistence of parasite DNA at
least until day 111 post inoculation. Immunosuppression by cyclophosphamide
treatment increased the parasitaemia, prevented the acute myocarditis and the
sympathetic denervation without significant alteration of the myocardial
parasitism. These results argue against a direct role for parasite-derived
products and implicate the inflammatory cells in the denervation process. As
previous studies in juvenile animals have discarded an essential role for
radiosensitive cells, the macrophages remain as the possible effectors for the
T. cruzi-induced neuronal damage.
Cyclophosphamide (Cy) is an alkylating agent
widely used in cancer chemotherapy. It has a bimodal effect on the immune
system, depending on the dose and schedule of administration. We have previously
demonstrated that a single low dose of Cy has an antimetastatic effect, achieved
through immunomodulation, in lymphoma bearing rats. Such a treatment reduced the
splenic production of IL-10, TGF-beta, and NO, restoring the lymphoproliferative
capacity. A shift from immunosuppression to immunopotentiation induced by
low-dose Cy treatment was mainly mediated by a decrease in IL-10 production. The
present study focused on the analysis of the modulation of type-1 cytokine
levels by treatment with a single low dose of Cy and the effect these cytokines
(IL-2 and IFN-gamma) and IL-10 have on primary tumor and metastatic cell growth.
Our results suggest that a single low dose of Cy induces a Th2/Th1 shift in the
cytokine profile of lymphoma-bearing rats, which may be responsible for its
antimetastatic effect. A direct action of IL-10 as a growth factor and IFN-gamma
as a cytotoxic factor on metastatic cells is also shown.
ICA69 (islet cell Ag 69 kDa) is a
diabetes-associated autoantigen with high expression levels in beta cells &
brain. Its function is unknown, but knockout of its Caenorhabditis elegans
homologue, ric-19, compromised neurotransmission. We disrupted the murine gene,
ica-1, in 129-strain mice. These animals aged normally, but speed-congenic
ICA69(null) nonobese diabetic (NOD) mice developed mid-life lethality,
reminiscent of NOD-specific, late lethal seizures in glutamic acid decarboxylase
65-deficient mice. In contrast to wild-type and heterozygous animals,
ICA69(null) NOD congenics fail to generate, even after immunization,
cross-reactive T cells that recognize the dominant Tep69 epitope in ICA69, and
its environmental mimicry Ag, the ABBOS epitope in BSA. This antigenic mimicry
is thus driven by the endogenous self Ag, and not initiated by the environmental
mimic. Insulitis, spontaneous, and adoptively transferred diabetes develop
normally in ICA69(null) NOD congenics. Like glutamic acid decarboxylase 65,
ICA69 is not an obligate autoantigen in diabetes. Unexpectedly, ICA69(null) NOD
mice were resistant to cyclophosphamide (CY)-accelerated diabetes.
Transplantation experiments with hemopoietic and islet tissue linked CY
resistance to ICA69 deficiency in islets. CY-accelerated diabetes involves not
only ablation of lymphoid cells, but ICA69-dependent drug toxicity in beta cells
that boosts autoreactivity in the regenerating lymphoid system.
The selective cytotoxic effect of CY on the
different T and B cell subsets results in modulation of the immune response in
... animals. The effect of these agents on nucleic acid synthesis led initial
investigators to classify them as immunosuppressants. The surprising finding of
Maguire and Ettore that CY augmented guinea pig immune response to contact
sensitizers compelled many investigators to test CYinduced immune stimulation in
their systems. CY can suppress antibody formation against a variety of antigens
when given 2-3 days after immunization. Similarly, when administered after the
antigen, CY can also suppress T cell mediated immunity generated against agents
producing contact sensitivity allografts and tumors. However, CY administration
prior antigen stimulation results in augmented T cell response against contact
sensitizing agents and hapten modified syngenetic cells. Under certain
conditions, CY can augment T cell mediated antitumor immunity and facilitate
adoptive transfer of antitumor immunity. CY, when administered just before or
just after tumor implantation, induces complete regression of a CY resistant
murine lymphoma growing in normal immunocompetent host. This regression was
immunologically mediated because equivalent CY doses have no effect on the
growth of this tumor in T cell deficient mice. ... The most likely mechanism by
which CY augments immune responses relates to preferential elimination of
suppressor and relative sparing of effector and helper cells. Thus, precursors
and mature murine suppressor cells are very sensitive to CY whereas the mature
effector cells are relatively insensitive. CY induced immunological regression
of murine leukemia is reversed by the infusion of normal spleen cells as a
source of precursors of suppressor cells. Memory and helper T cells are
relatively resistant to the cytotoxic effect of CY. NK activity against YAC
lymphoma targets by non T and non B cells is depressed by CY. Melphalan augments
antitumor immunity in a fashion similar to CY and increases ADCC. Nitrosoureas (BCNU)
have been shown to inhibit ADCC activity.
It appears that hepatic damage is minimized by
these secondary reactions, whereas significant amounts of the active
metabolites, such as 4-hydroxycyclophosphamide & its tautomer,
aldophosphamide, are transported to the target sites by the circulatory system.
In tumor cells, the aldophosphamide cleaves spontaneously, generating
stoichiometric amounts of phosphoramide mustard & acrolein. The former is
believed to be responsible for antitumor effects. The latter compound may be
responsible for the hemorrhagic cystitis seen during therapy with
cyclophosphamide.
Non-Human Toxicity Values:
LD50 Rat oral 160 mg/kg
LD50 Rat ip 40 mg/kg
LD50 Rat sc 144 mg/kg
LD50 Rat iv 148 mg/kg
LD50 Mouse oral 137 mg/kg
LD50 Mouse sc 200 mg/kg
LD50 Mouse iv 140 mg/kg
LD50 Mouse parenteral 315 mg/kg
Ongoing Test Status:
The NTP Toxicology Research and Testing
Program releases a Management Status Report on a quarterly basis. This report
gives the status of chemicals studied, under study, or proposed for study by NTP.
The 07/11/2001 issue indicates that the prechronic study for cyclophosphamide
monohydrate is completed, and the chemical is in review for further evaluation.
Route: gavage; Species: transgenic model evaluation, mice. /Cyclophosphamide
monohydrate/
The NTP Toxicology Research and Testing
Program releases a Management Status Report on a quarterly basis. This report
gives the status of chemicals studied, under study, or proposed for study by NTP.
The 07/11/2001 issue indicates that the prechronic study for cyclophosphamide
monohydrate is completed, and the chemical is in review for further evaluation.
Route: topical; Species: transgenic model evaluation, mice. /Cyclophosphamide
monohydrate/
TSCA Test Submissions:
Cyclophosphamide (CAS # 50-18-0) was evaluated
for chromosomal effects. The test substance was examined in an in vitro
cytogenetic assay with Chinese hamster ovary (CHO) cells with and without S-9
metabolic activation. It was determined that the test substance can be detected
as a promutagen efficiently using this method. No further information was
available due to the poor reading quality of the document.
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
... /Cyclophosphamide/ is activated by the
hepatic cytochrome P450 system. Cyclophosphamide is first converted to
4-hydroxycyclophosphamide, which is in a steady state with the acyclic tautomer
aldophosphamide. In vitro studies with human liver microsones & cloned P450
isoenzymes have shown that cyclophosphamide is activated by the CYP2B group of
P450 isoenzymes... . 4-hydroxycyclophosphamide may be oxidized further by
aldehyde oxidase either in liver or in tumor tissue & perhaps by other
enzymes, yielding the metabolites carboxyphosphamide &
4-ketocyclophsphamide, neither of which possesses significant biological
activity. It appears that hepatic damage is minimized by theses secondary
reactions, whereas significantl amoutns of the active metabolies, such as
4-hydroxycyclophosphamide & its tautomer, aldophosphamed, are transported to
the target sites by the circulatory system. In tumor cells, the aldophosphamide
cleaves spontaneously, generating stoichiometric amounts of phosphoramide
mustard & acrolein. The former is believed to be responsible for antitumor
effects. The latter cmpd may be responsible for the hemorrhagic cystitis seen
during therapy with cyclophosphamide. Cystitis can be reduced in intensity or
prevented by the pareneteral admin of mesna, a sulfhydryl cmpd that reacts
readily with acrolein in the acid environment of the urinary tract. ... Urinary
& fecal recovery of unchanged cyclophosphamide is minimal after iv admin.
Maximal concns in plasma are achieved 1 hr after oral admin, & the half-life
in plasma is about 7 hr.
SHEEP WERE ORALLY DOSED WITH CYCLOPHOSPHAMIDE.
IN COLLECTED URINE, 2 METABOLITES WERE OBSERVED AND CHARACTERIZED AS
O-(2-CARBOXYETHYL)-N,N-BIS (2-CHLOROETHYL)PHOSPHORODIAMIDATE
& 2-(BIS (2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZOPHOSPHORINE
2,4-DIOXIDE (4-KETOCYCLOPHOSPHAMIDE).
A REACTIVE METABOLITE, N,N-BIS-(2-CHLOROETHYL)PHOSPHORODIAMIDIC
ACID, WHICH POSSESSES POTENT ALKYLATING & CYTOTOXIC PROPERTIES, HAS RECENTLY
BEEN ISOLATED FROM THE OXYGENATION PRODUCTS OF CYCLOPHOSPHAMIDE AND MOUSE LIVER
MICROCHROMOSOMES.
Cyclophosphamide is well absorbed orally, and
peak plasma levels appear about one hour after oral use. It is also administered
intravenously. This drug is metabolized in the liver to the cytotoxic
metabolite, 4-hydroxycyclophosphamide, which is in equilibrium with the acyclic
tautomer, aldophosphamide. Although the major fraction of these metabolites is
oxidized further to inactive products, some aldophosphamide is converted to
phophoramidemustard, which alkylates DNA, and to acrolein.
Acrolein is the metabolite of cyclophosphamide
(CP) believed to be involved in the bladder toxicity associated with this
anticancer drug. The mechanism by which this extremely reactive intermediate is
delivered to the bladder is not known. Glutathione (GSH) readily conjugates with
acrolein, and the acrolein mercapturate 5-(3-hydroxypropyl)-N-acetylcysteine
(3-hydroxy-PrMCA) has been found in the urine of animals and man given CP. The
objectives of this study were to prepare and characterize synthetic standards of
the GSH acrolein adduct (3-oxopropyl)glutathione (3-oxoPrGSH), the acrolein
mercapturates S-(3-oxopropyl)-N-acetylcysteine (3-oxoPrMCA) and 3-hydroxyPrMCA,
and the S-oxidation product of 3-oxoPrMCA (3-oxoPrMCA S-oxide). In addition, the
release of acrolein from, and the bladder toxicity of, these conjugates was
determined. 3-OxoPrGSH and 3-oxoPrMCA were prepared with a 99% yield by
condensing acrolein with GSH and N-acetylcysteine, respectively.
An important feature of cytochrome P450 (CYP)
2B1 is its high ability to convert the prodrug cyclophosphamide (CPA) to
therapeutically cytotoxic metabolites, resulting in interstrand
DNA-cross-linking & cell death. We have examined whether & how the
phosphorylation of CYP2B1 influences CPA metabolic activation in vitro & in
vivo. We found first that only part of the total CYP2B1 pool undergoes
phosphorylation. This part is fully inactivated. Second, phosphorylation of
CYP2B1 in intact hepatocytes reduced by up to 75% toxification of CPA to
mutagenic metabolites (totally dependent on the same preferentially
CYP2B-catalyzed 4-hydroxylation of CPA as is the generation of highly cytotoxic
species). Third, the phosphoacceptor-serine 128 of CYP2B1 in the consensus
sequence for interaction with the protein kinase A represents an on/off switch
for the activation of CPA depending on the phosphorylation conditions in the
cell. Fourth, evidence is presented that the above-described events also occur
in vivo. In conclusion, a successful therapy with CPA, helped by forced
expression of CYP2B1 in tumor cells (as recently proposed) will, in addition, be
profoundly modified by its phosphorylation status.
Cyclophosphamide (CPA), a widely used
oxazaphosphorine anti-cancer prodrug, is inactive until it is metabolized by
cytochrome P450 to yield phosphoramide mustard and acrolein, which alkylate DNA
and proteins, respectively. Tumor cells transduced with the human cytochrome
P450 gene CYP2B6 are greatly sensitized to CPA, however, the pathway of
CPA-induced cell death is unknown. The present study investigates the cytotoxic
events induced by CPA in 9L gliosarcoma cells retrovirally transduced with
CYP2B6, or induced in wild-type 9L cells treated with mafosfamide (MFA) or
4-hydroperoxyifosfamide (4OOH-IFA), chemically activated forms of CPA and its
isomer ifosfamide. CPA and MFA were both shown to effect tumor cell death by
stimulating apoptosis, as evidenced by the induction of plasma membrane blebbing,
DNA fragmentation, and cleavage of the caspase 3 and caspase 7 substrate
poly(ADP-ribose) polymerase (PARP) in drug-treated cells. Caspase 9 was
identified as the regulatory upstream caspase activated in 9L cells treated with
CPA, MFA, or 4OOH-IFA, implicating the mitochondrial apoptotic pathway in
oxazaphosphorine-induced tumor cell death. Correspondingly, expression of the
mitochondrial proapoptotic factor Bax enhanced caspase 9 activation, plasma
membrane blebbing, and drug-induced cytotoxicity. Conversely, overexpression of
the mitochondrial antiapoptotic factor Bcl-2 blocked caspase 9 activation,
leading to an inhibition of drug-induced plasma membrane permeability and
blebbing, terminal deoxynucleotidyl transferase dUTP nick-end labeling
positivity, PARP cleavage, Annexin V positivity, and drug-induced cell death.
Although Bcl-2 thus blocked the cytotoxic effects of activated CPA, it did not
inhibit the drug's cytostatic effects. CPA induced S-phase cell cycle arrest
followed by conversion to an apoptotic pre-G1 state in wild-type 9L cells; by
contrast, Bcl-2-expressing 9L cells accumulated in G2/M in response to CPA
treatment. Intratumoral expression of Bcl-2 and related family members,
including both apoptotic and antiapoptotic factors, is thus an important
determinant of the responsiveness of tumor cells to CPA and ifosfamide, both in
the context of conventional chemotherapy and in patients sensitized to these
oxazaphosphorine drugs by the use of cytochrome P450-based gene therapy.
Specimens of whole bronchial tissue from the
main or lobar bronchi and peripheral parenchyma were removed at surgery of 21
male patients undergoing lung resection for lung cancer (n= 18) or other, non-neoplastic,lung
diseases (n= 3). Post-mitochondrial S-12 fractions were obtained. In parallel,
the same preparations were used to assess the activation of a promutagen,
cyclophosphamide (CPA, 4000 ug/plate), to metabolites reverting his(-)
Salmonella typhymurium strain TA1535. Parenchyma compared favorably to bronchus
preparations in activating CPA to mutagenic metabolites (n= 6 paired
observations).
Absorption, Distribution & Excretion:
Cyclophosphamide is well absorbed orally.
PLACENTAL TRANSFER OF
(14)CARBON-CYCLOPHOSPHAMIDE HAS BEEN DEMONSTRATED IN MICE; AND A POSITIVE
CORRELATION BETWEEN THE ALKYLATION OF EMBRYONIC DNA AND PRODUCTION OF CONGENITAL
ABNORMALITIES IN MICE HAS BEEN REPORTED. A SIMILAR CORRELATION HAS BEEN FOUND
FOR NUCLEAR-DNA-DEPENDENT RNA POLYMERASES IN RAT EMBRYOS. IN MOST SPECIES,
CYCLOSPHSPHAMIDE IS RAPIDLY ABSORBED, METABOLIZED AND EXCRETED. IN RATS, THE
SPECIFIC ACTIVITY IN TISSUES IS HIGHEST WITHIN 20-30 MIN FOLLOWING IP INJECTION;
UP TO 75% OF THE RADIOACTIVITY IS EXCRETED WITHIN 5-8 HR. /MONOHYDRATE/
AFTER ITS IV INJECTION, THE DRUG IS RAPIDLY
ABSORBED FROM THE BLOOD. IN PATIENTS RECEIVING 6.7-80 MG/KG BODY WT PER DAY OF
RING LABELLED CYCLOPHOSPHAMIDE, RADIOACTIVITY WAS DISTRIBUTED RAPIDLY TO ALL
TISSUES: ITS HALF LIFE IN THE PLASMA WAS 6.5 HOURS. NO RADIOACTIVITY WAS FOUND
IN THE EXPIRED AIR OR FECES. RECOVERY OF RADIOACTIVITY IN URINE HAS BEEN
REPORTED TO BE BETWEEN 50-68%, MAINLY IN THE FORM OF CARBOXYPHOSPHAMIDE AND
PHOSPHORAMIDE MUSTARD; 10-40% OF THE DRUG WAS EXCRETED UNCHANGED; AND 56% OF THE
REACTIVE METABOLITES WERE BOUND TO PLASMA PROTEINS. /MONOHYDRATE/
In a cross sectional study, the urine of 20
hospital workers occupationally exposed to cyclophosphamide and 21 unexposed
controls was monitored for excretion of cyclophosphamide. During the week in
which samples were collected, most of the workers handled cyclophosphamide fewer
than 5 times and the amount handled each time ranged from 100-1000 mg (mean + or
- 350 mg). All workers claimed to have taken regular safety precautions; ie, at
least wearing gloves during handling. The drug was identified in 5 cases (range:
0.7-2.5 ug cyclophosphamide excreted/24 hr urine). A clear relationship between
cyclophosphamide handling and urinary detection was shown. 4 of 5 persons with
detectable urinary cyclophosphamide had handled cyclophosphamide 10 times or
more during the week.
A group of four adult male Sprague Dawley rats
received each a bolus iv injection of (14)C-cyclophosphamide (50 uCi/rat) and 10
mg/kg of cyclophosphamide, dissolved in saline. Samples of plasma, seminal
fluid, and tissues were obtained and analyzed. Cyclophosphamide was first found
in seminal vesicle fluid within 10 min and reached equilibrium with plasma
radioactivity within 30 min. These concentrations were maintained after drug
administration for at least 2 hr. In a second experiment, male rats received an
ip injection of cyclophosphamide in saline (10 mg/kg unlabeled cyclophosphamide
plus 50 uCi/rat of (14)C-cyclophosphamide) 1 hr before exposure to females. The
males were killed and blood, urine, and seminal fluid samples were obtained.
Females were killed and uterus content plus several tissues were obtained for
analysis. More than 5 hr after the males received an ip injection of
14(C)-cyclophosphamide the radiolabeled drug was transmitted to the females and
was widely distributed in their seminal plug, vagina, cervix, kidney, and other
tissues. In a third experiment, groups of 10 male rats were injected ip with 10,
30, or 100 mg/kg cyclophosphamide in saline, and controls were given saline.
Each male was mated with 2 females. On day 20 of gestation, fetuses were removed
and studied. The number of pregnant females per sperm positive females ranged
from 73 to 92%, with no significant difference in any of the treated groups. The
number of implantations per pregnant female decreased with cyclophosphamide
treatment and at 30 mg/kg, this decrease was significantly different from
controls. The highest dose of cyclophosphamide increased the preimplantation
loss per litter, while the percentage of implantation loss per total corpora
lutea was almost doubled.
Cyclophosphamide is excreted into breast milk.
Oral bioavailability approximately =100%; must
be activated in liver by microsomal enzymes to active compds & toxic
metabolites; renal elimination of 22% parent drug & 60% of metabolites; t1/2
= 3-10 hr (parent); 6.5- >or=8 hr (alkylating activity) /from table/
Biological Half-Life:
Maximal concns in plasma are achieved 1 hr
after oral admin, & the half-life in plasma is about 7 hr.
Mechanism of Action:
The chemotherapeutic alkylating agents have in
common the property of becoming strong electrophiles through the formation of
carbonium ion intermediates or of transition complexes with the target
molecules. These reactions result in the formation of covalent linkages by
alkylation of various nucleophilic moieties such as phosphate, amino, sulfhydryl,
hydroxyl, carboxyl, & imidazole groups. The chemotherapeutic & cytotoxic
effects are directly related to the alkylation of DNA. The 7 nitrogen atom of
guanine is particularly susceptible to the formation of a covalent bond with
bifunctional alkylating agents & may well represent the key target that
determines their biological effects. It must be appreciated, however, that other
atoms in the purine & pyrimidine bases of DNA- particularly, the 1 & 3
nitrogens of adenine, the 3 nitrogen of cytosine, & the 6 oxygen of guanine-
also may be alkylated, as will be the phosphate atoms of the DNA chains &
amino & sulfhydryl groups of proteins. /Alkylating agents/
Cyclophosphamide can be used to cause
immunologically mediated regression of the immunogenic,
cyclophosphamide-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice
(B6D2F1 (C57BL/6 x DBA/2) females). In order to cause tumor regression it was
necessary to give cyclophosphamide (125-200 mg/kg of body wt, iv shortly before
or shortly after tumor implantation. Regardless of whether cyclophosphamide was
given before or after tumor implantation, tumor regression was associated with
the presence in the spleen of an incr number of Lyt-2+ T-cells capable of
passively transferring immunity to tumor bearing recipients. This augmented
level of immunity was sustained throughout the period of tumor regression. In
contrast, a lower level of concomitant immunity generated by control tumor
bearers decayed after day 12 of tumor growth. Because the therapeutic effect of
cyclophosphamide could be inhibited by passive transfer of L3T4+ T-cells from
normal donor mice it is apparent that the therapeutic effect of cyclophosphamide
is based on its ability to preferentially destroy L3T4+ suppressor T-cells.
These putative precursor suppressor T-cells were regenerated 4 days after being
destroyed by cyclophosphamide.
These studies enable the pattern of emesis and
nausea for 3 days following high-dose cyclophosphamide to be described and give
some insight into the mechanisms of emesis which may be operating. Nausea and
vomiting induced by cyclophosphamide-based chemotherapy has long latency of
onset (8-13 hr) and continues for at least 3 days. These findings are of
particular importance as many of these patients receive chemotherapy as
outpatients and emphasize the need for appropriate anti-emetic prophylaxis for
patients at home. Ondansetron was extremely effective over this time in the
control of emesis and nausea. These results suggest that high-dose
cyclophosphamide-induced emesis over days 1-3 is largely mediated via
5-hydroxytryptamine (5-HT) and 5-HT3 receptors.
The most likely mechanism by which
cyclophosphamide augments immune responses relates to preferential elimination
of suppressor and relative sparing of effector and helper cells. Thus,
precursors and mature murine suppressor cells are very sensitive to
cyclophosphamide whereas the mature effector cells are relatively insensitive
... . Cyclophosphamide induced immunological regression of murine leukemia is
reversed by the infusion of normal spleen cells as a source of precursors of
suppressor cells ... . Memory and helper T cells are relatively resistant to the
cytotoxic effect of cyclophosphamide ... . NK activity against YAC lymphoma
targets by non T and non B cells is depressed by cyclophosphamide ... .
Interactions:
PRIOR TREATMENT WITH ALLOPURINOL SIGNIFICANTLY
PROLONGS /THE HALF-LIFE OF CYCLOPHOSPHAMIDE/.
CYCLOPHOSPHAMIDE MAY ENHANCE NEUROMUSCULAR
BLOCKADE PRODUCED BY SUCCINYLCHOLINE BY INHIBITING ITS METABOLISM.
THE ENZYME INHIBITOR SKF 525-A, WHICH
INCREASES THE TERATOGENICITY OF CYCLOPHOSPHAMIDE, CAUSED AN INCREASE IN THE
CONCN OF CYCLOPHOSPHAMIDE IN THE MOUSE EMBRYO & ALSO CAUSED A DECREASE IN
METABOLITE FORMATION AFTER ADMIN OF CYCLOPHOSPHAMIDE TO PREGNANT MICE.
Cultured human osteosarcoma cell lines (OST
strain and HT 1080) and specimens obtained during surgery on humans (osteosarcoma,
malignant fibrous histiocytoma, rhabdomyosarcoma, epithelioid sarcoma,
mesenchymal chondrosarcoma, synovial sarcoma, leiomyosarcoma, and malignant
giant cell tumor) were used to study the synergistic effect of caffeine on
anticancer drugs, including cyclophosphamide as its active form
4-hydroxyperoxycyclophosphamide. Cell concentrations were 10,000 per dish for
the osteosarcoma strain, 50,000 per dish for the HT 1080 strain, and 100,000 to
500,000 for the fresh cells. After a 1 hour exposure of the cells to the
anticancer agent, caffeine was added to the top layer for the subsequent 10 day
to 3 week combined exposure. Treatment with 3.0 ug/ml (1/10 of the usual peak
plasma concentration) cyclophosphamide alone showed colony inhibition of 14.2%
in the OST strain and 8.5% in the HT 1080 strain. Addition of 0.2 mM caffeine
showed synergism, 27.8% and 56.2% inhibition, respectively. When 2 mM caffeine
was used with cyclophosphamide, colony inhibition was 57.1% in the OST strain.
At a cyclophosphamide concentration of 0.3 ug/ml and either 0.2 or 2 mM
caffeine, synergism still was observed. Using fresh human tumor specimens with
cyclophosphamide alone (3.0 ug/ml) 4 of 18 specimens showed positive
sensitivity. With 2 mM caffeine exposure in combination, 8 of 18 specimens
(44.4%) showed a significant synergistic effect; of these, 7 showed positive
sensitivity. An additive effect was observed in one specimen and a subadditive
effect in 3 specimens. Continuous exposure to 0.2 mM caffeine in combination
resulted in significant synergism in specimens. For comparison, caffeine alone
at 0.2 mM produced colony inhibition of 9.2% (OST strain) and 12.5% (HT 10890
strain) in the cultured cells; at 2.0 mM, 15.0% (OST strain) and 100.0% (HT 1080
strain). In fresh sarcoma specimens, caffeine alone at 2 mM produced inhibition
of 0.0% to 48.2% (mean, 19.1%) and there was no case with positive sensitivity.
DBA/2NCr1BR F1 mice received a single iv
injection of cyclophosphamide (70, 120 or 200 mg/kg) alone or 2 hr before an ip
injection of 1,000 mg/kg of diethyldithiocarbamate. 24 hr after, survival of
bone marrow colony forming units spleen and granulocyte macrophage colony
forming cells, was determined. On the whole, administration of
diethyldithiocarbamate reduced the toxic effect of cyclophosphamide on
hemopoietic progenitors. The effect was in general more evident at the lower
than at the higher doses of the antitumor drug.
Leukopenic and/or thrombocytopenic effects of
cyclophosphamide may be increased with concurrent use or recent therapy if these
medications /blood dyscrasia-causing medications/ cause the same effects; dosage
adjustment of cyclophosphamide, if necessary, should be based on blood counts.
Additive bone marrow depression may occur;
dosage reduction may be required when two or more bone marrow depressants,
including radiation, are used concurrently or consecutively /with
cyclophosphamide/.
Cyclophosphamide may raise the concentration
of blood uric acid; dosage adjustment of antigout agents /allopurinol or
colchicine or probenecid or sulfinpyrazone/ my be necessary to control
hyperuricemia and gout; uricosuric antigout agents may increase risk of uric
acid nephropathy. Concurrent use with allopurinol may enhance the bone marrow
toxicity of cyclophosphamide; if concurrent use is required, close observation
of toxic effects should be considered.
Inhibition of cholinesterase activity by
cyclophosphamide reduces or slows cocaine metabolism, thereby increasing and/or
prolonging its effects and increasing the risk of toxicity.
Concurrent use of high-dose cytarabine with
cyclophosphamide for bone marrow transplant preparation has bee reported to
result in an increase in cardiomyopathy with subsequent death.
Concurrent use /of daunorubicin or doxorubicin/
with cyclophosphamide may result in increased cardiotoxicity; it is recommended
that the total dose of daunorubicin or doxorubicin not exceed 400 mg/sq m of
body surface.
These agents /hepatic enzyme inducers/ may
induce microsomal metabolism to increase formation of alkylating metabolites of
cyclophosphamide, thereby reducing the half-life and increasing the activity of
cyclophosphamide.
Concurrent use of other immunosuppressants
such as: azathioprine; chlorambucil; corticosteroids, glucocorticoid;
cyclosporine; mercaptopurine; muromonab-CD3/ with cyclophosphamide may increase
the risk of infection and development of neoplasms.
Concurrent use /of lovastatin with
cyclophosphamide/ in cardiac transplant patients may be associated with an
increased risk of rhabdomyolysis and acute renal failure.
Cyclophosphamide may decrease plasma
concentrations or activity of pseudocholinesterase, the enzyme that metabolizes
succinylcholine, thereby enhancing the neuromuscular blockage of succinylcholine.
Increased or prolonged respiratory depression or paralysis (apnea) may occur but
is of minor clinical significance while the patient is being mechanically
ventilated; however, caution and careful monitoring of the patient are
recommended during and following concurrent or sequential use, especially if
there is a possibility of incomplete reversal of neuromuscular blockage
postoperatively.
The effect of high molecular
carboxymethyl-chitin-glucan (CMCG), admin either ip, iv or orally prior to
cyclophosphamide injection, on the frequency of micronucleated reticulocytes was
evaluated in peripheral blood of female ICR mice. Both ip and iv admin of CMCG
decreased the clastogenic effect of cyclophosphamide. The protective effect of
CMCG was concn dependent, with a higher decrease achieved by 100 mg/kg than by
50 mg/kg body weight. On the other hand, no even five peroral pretreatments with
CMCG in the dose of 200 mg/kg body weight during the week prior to simultaneous
admin of CMCG and cyclophosphamide induced a decrease of micronucleated
reticulocytes in peripheral blood.
Synergistically enhanced sister chromatid
exchange (SCE) frequency by cyclophosphamide (CP) was observed when L1210
lymphoid tumor cells were exposed in vivo to a non-toxic concn of
3-aminobenzamide (3-AB). Additive effects in SCE induction in vivo were observed
when either Ehrlich ascites tumor (EAT) cells or P388 lymphocytic leukemia cells
treated with CP were exposed to 3-AB in vivo. 3-AB enhanced the survival time of
L1210 tumor bearing BDF1 mice treated with CP. However, the combined CP plus
3-AB treatment did not increase the survival of either EAT BALB/c- or P388
BDF1-tumor bearing mice compared with the effect on survival by CP alone.
Therefore the in vivo differential antitumor effect, by CP in conjunction with
3-AB, appears to correlated well with the in vivo differential effect on
cytogenetic damage caused by the combined CP plus 3-AB treatment. In the
Salmonella typhimurium/mammalian microsome test CP appears to have a dose
dependent ability to induce base-pair substitutions in strains TA 100 and TA
1535 and frameshift mutations in strains TA 98 and TA 1537. Both types of
mutation were synergistically increased in the presence of 3-AB.
Treatment with Caralluma tuberculata extract
induced complex biochemical and cytological changes in mice. Its cytotoxicity in
the bone marrow cells of mice was comparable with that of the standard drug
cyclophosphamide (C); however, unlike C, C. tuberculata was not clastogenic (as
shown by the micronucleus assay). A dose-dependent decrease in the RNA content
of liver and testes was produced by C. tuberculata treatment whereas there was
no effect on the content of nucleic acid and protein in the brain. In the
extract-treated animals there was a significant and dose-dependent increase in
the DNA content of the liver, with a negligible effect on the protein content.
Combined treatment with C. tuberculata and C showed that C. tuberculata
diminished the effect of C on DNA levels; however, RNA levels were further
suppressed, resulting in increased cytotoxicity. Pretreatment with C.
tuberculata extract significantly reduced the clastogenicity of C. These results
indicated the involvement of different phytoconstituents acting by different
routes.
The effect of pretreatment with
carboxymethylglucan (CMG) on the frequency of micronuclei induced by
cyclophosphamide administration in mice was evaluated. Two doses of CMG (50
mg/kg body weight) injected either intraperitoneally 24 hr or intravenously 1 hr
prior to two cyclophosphamide administrations (80 mg/kg) significantly decreased
the frequency of micronucleated PCE in bone marrow. Of two evaluated derivatives
of carboxymethylglucan, the K3 derivative was most efficient. The results show
that it is possible to achieve a suppressive effect of soluble
carboxymethylglucan prepared from Saccharomyces cerevisiae against
cyclophosphamide mutagenicity. The notion may be useful for glucan's effects
against pharmacocarcinogenesis. Therapeutic application of glucan with
cyclophosphamide therapy may provide a remarkable decrease of the secondary
tumor risk. The utilization of these results for human patients needs to be
considered.
The modulatory effect of vitamin C (Vit C) on
the mutagenic effect of the antineoplastic drug cyclophosphamide (CP) was
assessed in the in vivo micronucleus test in Swiss mice. Simultaneous oral
administration of Vit C with ip administration of CP was found to decrease the
frequency of micronucleated polychromatic erythrocytes elevated by CP. Vit C
exhibited a significant antimutagenic effect over a wide dose range (1.56-200
mg/kg). The dose-response relationship was highly significant. These results
demonstrated the ability of the in vivo micronucleus test to detect in vivo
modulation of CP mutagenicity by Vit C. Our earlier results and those from other
laboratories also indicate that this model system is suitable for primary in
vivo screening of modulation of mutagenesis.
A total of 78 patients with second recurrence
or progression of histologically verified breast cancer were treated with
single-agent cyclophosphamide given at 2.5 g/sq m by iv infusion every 3 wk
along with mesna support. All had previously been treated with epirubicin and
cisplatin or epirubicin alone. Toxicity was predominantly hematologic: WHO grade
III+IV toxicity was found in 95% of cases. The overall response rate was 26.7%
(95% CI, 15.8-41.4%), with 7% of patients achieving a complete response (CR) and
19.7%, a partial response (PR). The median duration of CRs and PRs was 11 and 5
mo, respectively. The response rate observed for patients previously treated
with epirubicin alone was 30.5% in contrast to the 8.3% recorded for patients
previously treated with cisplatin plus epirubicin. Thus, an indication of
cross-resistance was absent between cyclophosphamide and epirubicin but possible
between cyclophosphamide and cisplatin.
The effect of WR-2721 against
cyclophosphamide-induced clastogenicity was studied using the in vivo
micronucleus assay. The frequency of micronuclei in polychromatic erythrocytes
in the peripheral blood of mice treated with WR-2721 and cyclophosphamide (CP),
each of the cmpd at a dose of 200 mg/kg body weight, was evaluated during the
15-day period. The suppressing effect of WR-2721, given 30 min prior to CP
admin, on micronuclei induced by the alkylating agent was demonstrated ... The
modulatory effect of WR-2721 on the clastogenic activity of CP in the
erythropoietic system by the mouse micronucleus test was shown.
/It was/ ... demonstrated in an earlier paper
that capsaicin, the pungent principle of red hot chili, has a potent
anti-oxidant property that interferes with free-radical involved mechanisms. In
the present paper we demonstrate that capsaicin significantly inhibits
cyclophosphamide-induced (ip) chromosomal aberrations and DNA strand breakages.
This protective action of capsaicin against CP-induced toxicity may possibly be
linked with its already reported 'desensitization' effect against chemical
irritant-induced damages.
In the rat, the mortality from
cyclophosphamide had prevented the administration of sufficient dosages to
produce detectible damage to stem spermatogonia. To overcome this problem, we
used bone marrow transplantation and sodium 2-mercaptoethanesulfonate (Mesna)
treatment to raise the lethal dose for 50% of the animals (LD50) for
cyclophosphamide from 275 to > 400 mg/kg body weight. In addition we used
irradiation, 2 weeks prior to injection of cyclophosphamide, to greatly enhance
the measured toxicity of cyclophosphamide towards stem spermatogonia. Whereas
sperm counts at 9 weeks after a 300 mg/kg cyclophosphamide dose were reduced by
only a factor of 1.6 without prior irradiation, they were reduced by a factor of
60 when 2.5 Gy of irradiation had been given. Dramatic protection against this
toxicity was produced by hormone treatment with a gonadotropin-releasing hormone
(GnRH) antagonist (Nal-Glu) and an antiandrogen (flutamide) following the
radiation but prior to cyclophosphamide. This hormone treatment did not modify
the stem cell toxicity of the radiation and it therefore must be protecting stem
cells against cyclophosphamide-induced damage.
Hamster to rat renal xenotransplantation was
performed with recipient nephrectomies. Recipients were treated beginning on day
0 with continuous FK 506 monotherapy, a 7-day or open-ended monotherapeutic
course of cyclophosphamide (CP), and the two drug regiments combined. CP alone
(10 mg/kg/day) prevented a xenospecific antibody response and tripled median
survival of the kidney (defined as recipient death) from 6 (control) to 18.5
days whereas FK 506 alone had no effect. The drugs in combination were no better
than CP alone (15 days) unless the 5-day course of CP was given at a higher dose
(15 mg/kg) and started 3 days preoperatively (79 days). In further experiments,
adjuvant measures were added to the minimally effective FK 506/7-day CP regimen
which gave a median survival of only 15 days. In the most successful
modification, intraoperative antibody depletion by the temporary transplantation
of third party hamster liver or en bloc kidneys increased median survival from
15 to 34 and 48 days, respectively. An intraoperative i.v. dose administration
of the anticomplement drug K76 instead of antibody depletion increased survival
to 26 days. Although the events of kidney rejection were similar to those of
heart xenografts and partially forestalled by the antibody inhibiting CP
treatment, or by antibody depletion, survival for > 100 days was accomplished
in only 5 of 86 treated animals.
Hemorrhagic cystitis is a common problem
following cyclophosphamide or radiation therapy. Chitosan has been shown to be
an effective hemostatic agent and promoter of wound healing in animal
experiments. We evaluated the safety and efficacy of intravesical chitosan in an
animal model of cyclophosphamide cystitis. Hemorrhagic cystitis was induced in
female F344 rats by intraperitoneal cyclophosphamide, 100 mg/kg Chitosan soln
(0.3 ml) was instilled intravesically on day 1 (Group 1), on days 1, 3, and 5
(Group 2), or 1 hr after the admin of cyclophosphamide (Group 3). The rats in
group 4 were treated with chitosan diluent on day 1 after cyclophosphamide, and
the rats in group 5 received intravesical chitosan without cyclophosphamide.
Sequential examination revealed decr mortality and lower incidences of severe
bladder bleeding, necrosis and inflammation in Group 3. Treatment delayed until
after the appearance of the cystitis, esp repeated treatments, appeared to make
the cyclophosphamide-induced changes worse. Used within 1 hr of cyclophosphamide
admin, before the cystitis develops, chitosan seemed to have the possibility to
inhibit the appearance of hemorrhagic cystitis. In addition to the changes in
the bladder, severe changes occurred in the kidneys secondary to
cyclophosphamide.
The effect of pretreatment with miltefosine
(MIL) on the antineoplastic activity of cyclophosphamide (CPA) was evaluated in
sc benzo(a)pyrene-induced sarcomas (BPS) of the rat. MIL alone had no
antineoplastic effect on this autochthonous tumor, but enhanced the
chemotherapeutic effect of CPA. Conversely, MIL counteracted the myelotoxicity
of CPA in normal adult rats. Although the nadir of the leucocyte count remained
unchanged, the recovery phase was considerably shortened, an effect which
resembled the pharmacological action of GM-CSF.
The effect of protein malnutrition and alcohol
consumption on the yield of chromosomal damage induced by cyclophosphamide (CP)
was studied. Chromosomal damage induced in bone marrow cells of BALB/c mice was
established by scoring the frequency of dicentric chromosomes in C-banded
slides. Results obtained showed that CP induced a significant incr of
chromosomal damage in comparison with untreated mice. In addition, the yield of
dicentric chromosomes was higher in mice fed with the hypoproteic diet. The
animals which received ethanol in drinking water before treatment with CP
exhibited the highest frequency of dicentric chromosomes, with no relation with
the diet.
Cyclophosphamide causes lung injury in rats
through its ability to generate free radicals with subsequent endothelial and
epithelial cell damage. In order to observe the protective effects of a potent
anti-inflammatory antioxidant, curcumin (diferuloyl methane) on
cyclophosphamide-induced early lung injury, healthy, pathogen free male Wistar
rats were exposed to 20 mg/100 g body weight of cyclophosphamide,
intraperitoneally as a single injection. Prior to cyclophosphamide intoxication
oral administration of curcumin was performed daily for 7 days. At various time
intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed
for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and
ascorbic acid Bronchoalveolar lavage fluid was analyzed for biochemical
constituents. The lavage cells were examined for lipid peroxidation and
glutathione content. Excised lungs were analyzed for antioxidant enzyme levels.
Biochemical analyses revealed time course increases in lavage fluid total
protein, albumin, angio+ensin converting enzyme (ACE), lactate dehydrogenase,
N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid
peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2,
3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid
peroxidation and decreased levels of glutathione and ascorbic acid were seen in
serum, lung tissue and lavage cells of cyclophosphamide groups. Serum
angiotensin converting enzyme activity increased which coincided with the
decrease in lung tissue levels. Activities of antioxidant enzymes were reduced
with time in the lungs of cyclophosphamide groups.
Therapeutic Uses:
Alkylating Agents; Antineoplastic Agents,
Alkylating; Antirheumatic Agents; Carcinogens; Immunosuppressive Agents;
Mutagens; Teratogens
MEDICATION (VET): ... CYTOTOXIC AGENT FOR
CARCINOMA, LEUKOSIS, ADENOMA, FIBROMA, & MIXED MAMMARY TUMORS OF DOGS ...
MYCOTIC DERMATITIS ... OF SHEEP & TRYPANOSOMIASIS ... OF CATTLE ... ALSO ...
CYTOTOXIC ... & IMMUNOSUPPRESSIVE IN RATS ... AGAINST EXPTL ALLERGIC
ENCEPHALOMYELITIS.
The clinical spectrum of activity for
cyclophosphamide is very broad. It is an essential component of many effective
drug combinations for non-Hodgkin's lymphomas. Complete remissions &
presumed cures have been reported when cyclophosphamide was given as a single
agent for Burkitt's lymphoma. It is frequently used in combination with
methotrexate (or doxorubicin) & fluorouracil as adjuvant therapy after
surgery for carcinoma of the breast. Notable advantages of this drug are the
availability of the oral route of admin & the possibility of giving
fractionated doses over prolonged periods. For these reasons it possesses a
versatility of action that allows an intermediate range of use, between that of
the highly reactive iv mechlorethamine & that of oral chlorambucil.
Beneficial results have been obtained in multiple myeloma; chronic lymphocytic
leukemia; carcinomas of the lung, breast, cervix, & ovary; &
neuroblastoma, retinoblastoma, & other neoplasms of childhood. Because of
its potent immunosuppressive properties, cyclophosphamide has received
considerable attention for the control of organ refection after transplantation
& in nonneoplastic disorders associated with altered immune reactivity,
including Wegener's granulomatosis, rheumatoid arthritis, & the nephrotic
syndrome in children.
Furosemide may improve, renal blood flow,
decrease resorption of sodium and chloride, and increase free water excretion.
The initial dose of furosemide is 2 mg/kg, IV. This dosage can be doubled or
tripled if urine output does not increase within 1 hr. However, if there is no
response to 6 mg/kg, another approach should be tried. If effective, furosemide
can be given parenterally at 2 mg/kg, tid., to maintain a diuresis.
/EXPL THER:/ To find out which anticancer
drugs could utilize to the best advantage a syngeneic bone marrow
transplantation (BMT) in high-dose chemotherapy for cancer, cyclophosphamide was
tested in Sprague Dawley rats. Two or three varying doses of cyclophosphamide
(100-400 mg/kg) were administered iv on day 0, followed by the injection of
syngeneic bone marrow cells (50,000,000, iv) on day 2, & the animals were
observed for over 60 days. A beneficial effect of bone marrow transplantation
was observed only with cyclophosphamide (300-400 mg/kg) & nimustine
hydrochloride (40 mg/kg). In order to enhance the beneficial effect of bone
marrow transplantation observed with cyclophosphamide & nimustine
hydrochloride, a way of drug admin was designed & carried out. Consequently
a higher survival rate was obtained in the following experimental groups;
(cyclophosphamide 200 mg/kg, days 0 & 1) + bone marrow transplantation >
(cyclophosphamide 400 mg/kg, day 0) + bone marrow transplantation, (nimustine
hydrochloride 20 mg/kg, days 0 & 1) + bone marrow transplantation > (nimustine
hydrochloride 40 mg/kg, day 0) + bone marrow transplantation; (cyclophosphamide
200 mg/kg + nimustine hydrochloride 20 mg/kg, day 0) + bone marrow
transplantation > (cyclophosphamide 400 mg/kg or nimustine hydrochloride 40
mg/kg, day 0) + bone marrow transplantation; (cyclophosphamide 200 mg/kg, day 0)
+ (nimustine hydrochloride 20/kg, day 1) + bone marrow transplantation > (nimustine
hydrochloride 20 mg/kg, day 0) + (cyclophosphamide 200 mg/kg, day 1) + bone
marrow transplantation.
Cyclophosphamide is indicated for treatment of
acute lymphoblastic (stem-cell) leukemia in children (including during remission
to prolong the duration), and for treatment of acute myelogenous and acute
monocytic leukemia. /Included in US product labeling/
Cyclophosphamide is indicated for treatment of
chronic granulocytic leukemia (it is usually ineffective in acute blastic
crisis) and chronic lymphocytic leukemia. /Included in US product labeling/
Cyclophosphamide is indicated for treatment of
adenocarcinoma of the ovary, breast carcinoma, neuroblastoma (in patients with
disseminated disease /NOT included in US product labeling/), retinoblastoma, ...
. /Included in US product labeling/
... /Cyclophosphamide is indicated for
treatment of/ small cell and non-small cell lung carcinoma, cervical carcinoma,
and for endometrial carcinoma, bladder carcinoma, prostatic carcinoma,
testicular carcinoma, and Wilms' tumor and adrenocortical carcinoma (Evidence
rating: IIID). /NOT included in US product labeling/
Cyclophosphamide is indicated for treatment of
Stage III and IV (Ann Arbor or Peter's Staging System) Hodgkin's disease and
non-Hodgkin's lymphomas including nodular or diffuse lymphocytic lymphoma,
mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma, (and
lymphoblastic lymphosarcoma /NOT included in US product labeling/). /Included in
US product labeling/
Cyclophosphamide is indicated for treatment of
multiple myeloma. /Included in US product labeling/
Cyclophosphamide is indicated for treatment of
advanced mycosis fungoides. /Included in US product labeling/
Cyclophosphamide is indicated as an
immunosuppressant in the treatment of steroid-resistant or frequently relapsing
steroid-sensitive biopsy proven minumal-change nephrotic syndrome in children
(and adults /NOT included in US product labeling/). /Included in US product
labeling/
Cyclophosphamide is indicated for treatment of
various sarcomas, including Ewing's sarcoma, osteosarcoma, and soft tissue
sarcomas. /NOT included in US product labeling/
Cyclophosphamide is indicated for treatment of
Waldenstrom's macroglobulinemia. /NOT included in US product labeling/
Cyclophosphamide is indicated as first-line
therapy, as a single agent or in combination with other chemotherapeutic agents,
for treatment of Histiocytosis X (Letterer-Siwe disease). (Evidence rating: IIID)
/NOT included in US product labeling/
Cyclophosphamide is indicated for treatment of
thymoma. /NOT included in US product labeling/
Cyclophosphamide is used for treatment of germ
cell ovarian, primary brain, and gestational trophoblastic tumors. /NOT included
in US product labeling/
Cyclophosphamide is used for its
immunosuppressant activity, for prevention of rejection in homotransplantation.
/NOT included in US product labeling/
Cyclophosphamide is used as an
immunosuppressant in the treatment of rheumatoid arthritis and other autoimmune
diseases such as polymyositis (systemic dermatomyositis), multiple sclerosis,
Wegener's granulomatosis, systemic lupus erythematosus, and other types of
vasculitis. /NOT included in US product labeling/
Cyclophosphamide is used as an antitumor agent
and experimentally for removal of fleece in adult sheep. The likelihood that
cyclophosphamide residues will occur or pose a problem is remote.
Severe aplastic anemia (SAA) can be
successfully treated with allogeneic bone marrow transplantation (BMT) or
immunosuppressive therapy. However, the majority of patients with SAA are not
eligible for BMT because they lack an HLA-identical sibling. Conventional
immunosuppressive therapy also has major limitations; many of its remissions are
incomplete and relapse or secondary clonal disease is common. Cyclophosphamide
is a potent immunosuppressive agent that is used in all BMT conditioning
regimens for patients with SAA. Preliminary evidence suggested that high-dose
cyclophosphamide, even without BMT, may be beneficial to patients with SAA.
Therefore, 10 patients with SAA and lacking an HLA-identical sibling were
treated with high-dose cyclophosphamide (45 mg/kg/day) for 4 consecutive days
with or without cyclosporine. A complete response (hemoglobin level, > 13 g/dL;
absolute neutrophil count, > 1.5 x 10(9)/L, and platelet count > 125 x
10(9)/L) was achieved in 7 of the 10 patients. One of the complete responders
died from the acquired immunodeficiency syndrome 44 months after treatment with
high-dose cyclophosphamide. The 6 remaining patients are alive and in continuous
complete remission, with a median follow-up of 10.8 years (range, 7.3 to 17.8
years). The median time to last platelet transfusion and time to 0.5 x 10(9)
neutrophils/L were 85 and 95 days, respectively. None of the complete responders
has relapsed or developed a clonal disease. These results suggest that high-dose
cyclophosphamide, even without BMT, may be more effective than conventional
immunosuppressive therapy in restoring normal hematopoiesis and preventing
relapse or secondary clonal disorders. Hence, further studies confirming the
efficacy of this approach in SAA are indicated.
The objective of this study was to determine
the tolerance and toxicities of high-dose cyclophosphamide (CPA) at 7 g/sq m
given in four fractions over 8 hr in children with advanced solid tumors ...
Twenty children aged 1 1/2-19 years (median, 12 years) received 24 courses of
high-dose CPA at 7 g/sq m for the treatment of advanced malignant solid tumor.
CPA was given in four l-hr infusions of 1.75 g/sq m each, with 1 hr of rest
between each dose. MESNA was used as a uroprotective agent and was continued for
24 hr after the final dose of CPA. With only one exception, all patients were
discharged at the end of MESNA infusion and received granulocyte
colony-stimulating factor, prophylactic ciprofloxacin, and co-trimoxazole ...
Severe but transient myelosuppression was observed. The median time to
neutrophil and platelet recovery was 17 and 19 days, respectively. Fever
developed after 13 of the 24 courses, and hospitalization was required.
Extramedullary toxicities were mild. No patient showed cardiomyopathy or
hemorrhagic cystitis. Forty-six percent of the courses were managed entirely on
an outpatient basis. Objective tumor response was seen in five patients ... CPA
at 7 g/sq m is well tolerated by children with advanced malignancies and should
be considered in earlier phases of antineoplastic therapy.
Cyclophosphamide (CTX) is an active drug in
breast cancer & presents a well-established dose-response relationship. To
explore further this relationship, the present pilot study investigated the
therapeutic efficacy of cyclophosphamide at intermediate dose in 2 groups of
untreated patients with advanced breast cancer. Nine women received the drug
alone at 3-4 g/sq m iv every 2 wk for a total of 3 doses. The same dose schedule
was also given to 11 women following the admin of 4 cycles of Adriamycin, at 75
mg/sq m iv every 3 wk. We documented 1 partial remission in untreated women
& 4 partial responses in Adriamycin-treated patients. The major toxicity was
represented by leukopenia & neutropenia. Myelosuppression was relevant but
of short duration, & the use of G-CSF appeared useful in controlling this
side effect. In spite of the high dose intensity of the present cyclophosphamide
dose schedule (9 g/sq m in 4 wk), i.e., almost 3 times superior to that
conventionally employed, present results do not suggest its superiority over the
current chemotherapeutic regimens utilized in advanced disease.
Antineoplastic
MEDICATION (VET): ANTINEOPLASTIC
HAS BEEN TESTED AS AN INSECT CHEMOSTERILANT.
/MONOHYDRATE/
... PROPOSED AS DEFLEECING AGENT FOR SHEEP.
Most first-line regimens /for treating ovarian
cancer/ currently include cisplatin & cyclophosphamide ... .
A 78-yr-old man was hospitalized on February
29, 2000 because of dyspnea. A chest radiograph showed diffuse bilateral
interstitial shadows associated with pulmonary volume loss. We could not obtain
histological evidence of idiopathic interstitial pneumonia (IIP) because of his
advanced age & severe respiratory dysfunction. IIP was diagnosed on the
basis of radiographic findings & clinical symptoms. The patient was
intubated & mechanical ventilation was performed. After one course of pulsed
cyclophosphamide (CPM) & methylprednisolone therapy, the hypoxemia improved
& it became possible to wean the patient from the ventilator. After 5
courses of pulsed CPM therapy, the dose of oral corticosteroid was tapered. CPM
was administered safely without any severe side effects. Pulsed CPM therapy
appears to be a viable alternative method of treatment for IIP.
Drug Warnings:
Appropriate caution is advised when the drug
is considered for use in ... /nonneoplastic/ conditions, not only because of its
acute toxic effects but also because of its high potential for inducing
sterility, teratogenic effects, & leukemia. ... Administration of the drug
should be interrupted at the first indication of dysuria or hematuria. The
syndrome of inappropriate secretion of antidiuretic hormone (ADH) has been
observed in patients receiving cyclophosphamide, usually at doses higher than 50
mg/kg. It is important to be aware of the possibility of water intoxication,
since these patients are usually vigorously hydrated.
POTENTIAL ADVERSE EFFECTS ON FETUS: Various
fetal malformations, especially skeletal defects and dysmorphic features, but
other chemotherapeutic agents given concurrently. POTENTIAL SIDE EFFECTS ON
BREAST-FED INFANT: Transient neutropenia from cyclophosphamide with prednisone
and vincristine. Potential mutagenicity, carcinogenicity, adverse effects on
fetus. FDA Category: D (D = There is evidence of human fetal risk, but the
potential benefits from use in pregnant women may be acceptable despite the
potential risks (e.g., if the drug is needed in a life-threatening situation or
for a serious disease for which safer drugs cannot be used or are ineffective.))
/from Table II/
Drugs that are Contraindicated during
Breast-Feeding: Cyclophosphamide: Possible immune suppression; unknown effect on
growth or association with carcinogenesis; neutropenia. /from Table 1./
THE DRUG IS MOST TOXIC TO THE HUMAN FETUS
DURING 1ST 3 MO & CONGENITAL ABNORMALITIES HAVE BEEN DETECTED AFTER IV
INJECTION OF LARGE DOSES TO PREGNANT WOMEN DURING THIS PERIOD OF PREGNANCY.
/MONOHYDRATE/
For routine clinical use, ample fluid intake
is recommended.
Cyclophosphamide is distributed into breast
milk. Breast-feeding is not recommended during chemotherapy because of the risks
to the infant (adverse effects, mutagenicity, carcinogenicity).
Prepubescent girls treated with
cyclophosphamide usually develop secondary sexual characteristics normally, have
regular menses, and subsequently conceive; however, ovarian fibrosis and
apparent complete loss of germ cells after prolonged treatment in late
prepubescence have been reported. Prepubescent boys treated with
cyclophosphamide develop secondary sexual characteristics normally, but may have
oligospermia or azoospermia, increased gonadotropin secretion, and some degree
of testicular atrophy; azoospermia may be reversible, although possibly not for
several years after the end of cyclophosphamide therapy.
Although appropriate studies on the
relationship of age to the effects of cyclophosphamide have not been performed
in the geriatric population, geriatrics-specific problems are not expected to
limit the usefulness of this medication in the elderly. However, elderly
patients are more likely to have age-related renal function impairment, which
may require caution in patients receiving cyclophosphamide.
The bone marrow depressant effects of
cyclophosphamide may result in an increased incidence of microbial infection,
delayed healing, and gingival bleeding. Dental work, whenever possible should be
completed prior to initiation of therapy or deferred until blood counts have
returned to normal. Patients should be instructed in proper oral hygiene during
treatment, including caution in use of regular tooth brushes, dental floss, and
toothpicks. Cyclophosphamide may also rarely cause stomatitis associated with
considerable discomfort.
Because normal defense mechanisms may be
suppressed by cyclophosphamide therapy, concurrent use with a live virus vaccine
may potentiate the replication of the vaccine virus, may increase the
side/adverse effects of the vaccine virus, and/or may decrease the patient's
antibody response to the vaccine; immunization of these patients should be
undertaken only with extreme caution after careful review of the patient's
hematologic status and only with the knowledge and consent of the physician
managing the cyclophosphamide therapy. The interval between discontinuation of
medication that cause immunosuppression and restoration of the patient's ability
to respond to the vaccine depends on the intensity and type of immunosuppression-causing
medications used, the underlying disease, and other factors; estimates vary from
3 months to 1 year. Patients with leukemia in remission should not receive live
virus vaccine until at least 3 months after their last chemotherapy. In
addition, immunization with oral polio-virus vaccine should be postponed in
persons in close contact with the patient, especially family members.
Anorexia, nausea, and vomiting occur commonly
with cyclophosphamide, especially at high doses; some clinicians reported that
these effects respond to treatment with antiemetics. Occasionally, diarrhea,
hemorrhagic colitis, mucosal irritation, and oral ulceration have been reported.
Rarely, aphthous stomatitis, enterocolitis, and hepatotoxicity as evidenced by
jaundice and hepatic dysfunction have occurred.
Alopecia occurs frequently in patients who
receive cyclophosphamide and patients should be forewarned of this possibility.
In usual doses, about 33% of patients who receive the drug experience alopecia,
generally beginning about 3 weeks after initiation of therapy; the condition is
usually reversible but new hair may be a different color or texture. Transverse
ridging, retarded growth, and/or pigmentation of fingernails may occur, as well
as skin pigmentation. Nonspecific dermatitis has also been reported.
Other reported adverse effects of
cyclophosphamide include headache, dizziness, and myxedema. Faintness, facial
flushing, diaphoresis, and oropharyngeal sensation have occurred following IV
administration of cyclophosphamide, have been reported. The drug may interfere
with normal wound healing.
Some patients who have received
cyclophosphamide alone, as part of a combination regimen, or as adjunctive
therapy have developed secondary malignancies, most frequently urinary bladder,
myeloproliferative, & lymphoproliferative malignancies. Although a causal
relationship has not been definitely established, the possibility of development
of a secondary malignancy should be considered in weighing the possible benefit
from the drug against the potential risk. Secondary malignancies have occurred
most frequently in patients who have been treated with cyclophosphamide for
primary myeloproliferative & lymphoproliferative malignancies & primary
nonmalignant diseases in which immune processes are believed to be involved.
Secondary urinary bladder malignancies generally have occurred in patients who
previously developed hemorrhagic cystitis. In some cases, the secondary
malignancy was not detected until several years after discontinuance of
cyclophosphamide therapy. Long-term follow-up of women who received
cyclophosphamide-containing adjuvant chemotherapy regimens for the treatment of
early breast cancer indicates that the incidence of other solid tumors &
secondary leukemia in these women is not substantially greater than that in the
general population.
CAREFUL EVALUATION OF BONE MARROW FUNCTION IS
IMPERATIVE AND PROLONGED THERAPY IS GUIDED BY KEEPING THE TOTAL LEUKOCYTE COUNT
BETWEEN 2500 AND 4000 CELLS PER CUBIC MILLIMETER OF BLOOD OR BY OBTAINING THE
DESIRED RESPONSE OF THE TUMOR.
Potentially fatal cardiotoxicity also has
occurred when cyclophosphamide (given concomitantly with mesna /2-mercaptoethane
sulfonic acid sodium salt/ and followed with autologous bone marrow transplant)
was administered inadvertently in a dosage of 4 g/sq m daily for 4 doses rather
than in a total dose of 4 g/sq m administered over 4 days in equally divided
doses of 1 g/sq m daily as part of a phase I protocol.
One of the major and dose limiting adverse
effects of cyclophosphamide is hematologic toxicity, which is usually reversible
after discontinuance of the drug. Hematopoietic adverse effects include
leukopenia, thrombocytopenia, hypothrombinemia, and anemia. Leukopenia is
considered to be an expected effect of cyclophosphamide therapy and may be
severe. Leukopenia nadirs generally occur at 8-15 days following a single dose
of cyclophosphamide and recovery usually occurs within 17-28 days.
Thrombocytopenia is reportedly less common, with nadirs occurring 10-15 days
after administration of the drug. Anemia, particularly after large doses or
prolonged therapy, and rarely hypoprothrombinemia have been reported. Rarely,
cyclophosphamide has been reported to produce positive direct antiglobulin
(Coombs') test results and hemolytic anemia.
In children treated with cyclophosphamide a
transient blurring of vision has been reported in 5 out of 59, coming on in
minutes after intravenous injection in two and within 24 hours in the other
three. The duration of blurring ranged from one hour to two weeks, but vision
returned to normal in all.
Cyclophosphamide can cause sterility in people
of either sex. It can damage the germinal cells in prepubertal, pubertal and
adult males, and causes premature ovarian failure in females.
... To analyse the treatment-related
complications of busulphan and cyclophosphamide (BU-CY) as the conditioning
regimen for allogeneic peripheral blood stem cell transplantation (allo-PBSCT).
... The clinical data of 40 leukemia patients undergoing allo-PBSCT between June
1997 and May 1999 in our BMT center were retrospectively analysed. ... Recovery
of neutrophil and platelet was achieved at a median of day +13 (9 similar 28)
and day +12 (7 similar 60) respectively. Acute GVHD occurred in 17 of 40
patients (42.5%) with grade II-IV in 10 patients (25%). Chronic GVHD developed
in 21 out of 30 evaluable patients (70%). Mild to severe mucositis occurred in
30 patients (75%), and 4 of them had severe esophagitis with bleeding.
Haemorrhagic cystitis developed in 8/40 (20%) patients, the median time of its
onset was day +100 (+7 to +165). Six of 40 patients (15%) developed interstitial
pneumonia (IP), 5 of them were due to cytomegalovirus infection, and the
remaining one due to pneumocystis carinii infection. No hepatic veno-occlusive
disease was observed and no seizure occurred. During the median follow-up of 480
(300 similar 1000) days, 4 (10%) patients relapsed and 8 (20%) patients died of
the transplant-related complications. The 3 year leukemia-free survival rate was
70%. ... BU (domestic busulfan)-CY regimen is relatively easy to administer and
well tolerated, with low extramedullary toxicities.
... We now described five patients receiving
monthly cycles of iv CP /cyclophosphamide/ whose allergic reactions included
clinical features of type I hypersensitivity but were atypical in their markedly
delayed onset (i.e., 8 to 16 hr in patients 1 to 4 and 10 days in patient 5) ...
The objective was to investigate these late-developing clinical reactions by
skin testing with CP and two of its major metabolites ... The five patients and
a control group receiving iv CP uneventfully were studied by the same skin test
protocol ... The four individual in the control group were unreactive to CP or
its metabolites. All five patients with late-onset allergic reactions had
positive immediate skin test results to CP metabolites but not to CP itself. We
propose that the allergic reactions in patients 1 to 4 were mediated, wholly or
in major part, by IgE antibodies reactive with allergens derived from
time-dependent drug metabolites.
Sterile hemorrhagic cystitis has been reported
to occur in up to 20% of patients (especially children) on long-term
cyclophosphamide therapy. The effect, which rarely can be severe and even fatal,
is attributed to chemical irritation by active metabolites of cyclophosphamide
that accumulate in concentrated urine. Hematuria usually resolves spontaneously
within a few days after discontinuance of cyclophosphamide therapy but may
persist for several months. Fibrosis of the bladder (sometimes extensive), with
or without cystitis, also has occurred, but less frequently. Atypical epithelial
cells may be found in the urinary sediment. These adverse effects appear to be
related to the dosage and duration of cyclophosphamide therapy. Nephrotoxicity,
including hemorrhagic ureteritis and renal tubular necrosis, has been reported;
such lesions reportedly resolve in most instances following discontinuance of
cyclophosphamide therapy.
THERE HAVE BEEN AT LEAST 30 CASE REPORTS OF
MALIGNANCY IN PATIENTS TREATED WITH CYCLOPHOSPHAMIDE FOR NONMALIGNANT DISORDERS,
MAINLY RHEUMATOID ARTHRITIS AND CHRONIC GLOMERULONEPHRITIS. THESE INCLUDED 17
ACUTE NONLYMPHOCYTIC LEUKEMIAS, ONE CHRONIC NONLYMPHOCYTIC LEUKEMIA, ONE ACUTE
LYMPHOCYTIC LEUKEMIA, ONE CHRONIC LYMPHOCYTIC LEUKEMIA, TWO BLADDER CANCERS, ONE
SQUAMOUS CELL CANCER OF THE SKIN, THREE RETICULUM CELL SARCOMAS, ONE HODGKIN'S
DISEASE, ONE MELANOMA, TWO CEREBRAL GLIOMAS, ONE CERVICAL CANCER AND ONE PLEURAL
SARCOMA. /MONOHYDRATE/
Gonadal suppression, resulting in amenorrhea
or azoospermia, may occur in patients taking antineoplastic therapy, especially
with the alkylating agents. In general, these effects appear to be related to
dose & length of therapy & may be irreversible. Prediction of the degree
of testicular or ovarian function impairment is complicated by the common use of
combinations of several antineoplastics, which makes it difficult to assess the
effects of individual agents. However, there have been numerous reports of
gonadal suppression with use of cyclophosphamide, which seems to depend on dose,
duration, & state of gonadal function at the time of therapy, sterility may
be irreversible in some patients.
THERE WAS INCR IN NUMBER OF CHROMOSOMAL
ABERRATIONS IN THE PERIPHERAL BLOOD LYMPHOCYTES OF CHILDREN TREATED WITH
CYCLOPHOSPHAMIDE (3-5 MG/DAY FOR 6-8 MONTHS) FOR NONMALIGNANT CONDITIONS &
OF PATIENTS WITH RHEUMATOID ARTHRITIS FOLLOWING CYCLOPHOSPHAMIDE TREATMENT.
SIMILAR INCR WERE OBSERVED IN LYMPHOCYTES OF WOMEN WITH RECURRENT OVARIAN OR
UTERAL CARCINOMA 3 OR 24 HR AFTER AN IV ADMIN OF 2.0 G & IN THE BONE MARROW
& LYMPH NODE CELLS OF PATIENTS WITH LYMPHOGRANULOMATOSIS 24-72 HR AFTER
SINGLE DOSE OF 400 MG CYCLOPHOSPHAMIDE. INCR LEVELS OF SISTER CHROMATID EXCHANGE
IN PERIPHERAL BLOOD LYMPHOCYTES HAVE BEEN OBSERVED IN PATIENTS TREATED WITH
CYCLOPHOSPHAMIDE. THESE HAVE INCLUDED PATIENTS WITH MALIGNANT LYMPHOMA &
NEPHROTIC SYNDROME, A PATIENT WITH RETICULOSARCOMA, 3 PATIENTS WITH UNSPECIFIED
MALIGNANT TUMORS & 1 PATIENT WITH ACUTE GLOMERULONEPHRITIS. /MONOHYDRATE/
LEUKOPENIA IS INEVITABLE SIDE EFFECT & IS
USED AS INDEX OF DOSAGE ... HYPOPROTHROMBINEMIA ... .
Nausea & vomiting, myelosuppression with
platelet sparing, & alopecia are common to virtually all regimens using
cyclophosphamide. Mucosal ulcerations &, less frequently, interstitial
pulmonary fibrosis also may result from cyclophosphamide treatment.
Extravasation of the drug into subcutaneous tissues does not produce local
reactions, & thrombophlebitis does not complicate iv admin. The occurrence
of sterile hemorrhagic cystitis has been reported in 5%-10% of patients. As
noted above, this has been attributed to chemical irritation produced by
acrolein. Its incidence is significantly reduced by coadministration of mesna.
For routine clinical use, ample fluid intake is recommended. Admin of the drug
should be interrupted at the first indication of dysuria or hematuria. The
syndrome of inappropriate secretion of antidiuretic hormone (ADH) has been
observed in patients receiving cyclophosphamide, usually at doses higher then 50
mg/kg. It is important to be aware of the possibility of water intoxication,
since these patients usually are vigorously hydrated.
Interactions:
PRIOR TREATMENT WITH ALLOPURINOL SIGNIFICANTLY
PROLONGS /THE HALF-LIFE OF CYCLOPHOSPHAMIDE/.
CYCLOPHOSPHAMIDE MAY ENHANCE NEUROMUSCULAR
BLOCKADE PRODUCED BY SUCCINYLCHOLINE BY INHIBITING ITS METABOLISM.
THE ENZYME INHIBITOR SKF 525-A, WHICH
INCREASES THE TERATOGENICITY OF CYCLOPHOSPHAMIDE, CAUSED AN INCREASE IN THE
CONCN OF CYCLOPHOSPHAMIDE IN THE MOUSE EMBRYO & ALSO CAUSED A DECREASE IN
METABOLITE FORMATION AFTER ADMIN OF CYCLOPHOSPHAMIDE TO PREGNANT MICE.
Cultured human osteosarcoma cell lines (OST
strain and HT 1080) and specimens obtained during surgery on humans (osteosarcoma,
malignant fibrous histiocytoma, rhabdomyosarcoma, epithelioid sarcoma,
mesenchymal chondrosarcoma, synovial sarcoma, leiomyosarcoma, and malignant
giant cell tumor) were used to study the synergistic effect of caffeine on
anticancer drugs, including cyclophosphamide as its active form
4-hydroxyperoxycyclophosphamide. Cell concentrations were 10,000 per dish for
the osteosarcoma strain, 50,000 per dish for the HT 1080 strain, and 100,000 to
500,000 for the fresh cells. After a 1 hour exposure of the cells to the
anticancer agent, caffeine was added to the top layer for the subsequent 10 day
to 3 week combined exposure. Treatment with 3.0 ug/ml (1/10 of the usual peak
plasma concentration) cyclophosphamide alone showed colony inhibition of 14.2%
in the OST strain and 8.5% in the HT 1080 strain. Addition of 0.2 mM caffeine
showed synergism, 27.8% and 56.2% inhibition, respectively. When 2 mM caffeine
was used with cyclophosphamide, colony inhibition was 57.1% in the OST strain.
At a cyclophosphamide concentration of 0.3 ug/ml and either 0.2 or 2 mM
caffeine, synergism still was observed. Using fresh human tumor specimens with
cyclophosphamide alone (3.0 ug/ml) 4 of 18 specimens showed positive
sensitivity. With 2 mM caffeine exposure in combination, 8 of 18 specimens
(44.4%) showed a significant synergistic effect; of these, 7 showed positive
sensitivity. An additive effect was observed in one specimen and a subadditive
effect in 3 specimens. Continuous exposure to 0.2 mM caffeine in combination
resulted in significant synergism in specimens. For comparison, caffeine alone
at 0.2 mM produced colony inhibition of 9.2% (OST strain) and 12.5% (HT 10890
strain) in the cultured cells; at 2.0 mM, 15.0% (OST strain) and 100.0% (HT 1080
strain). In fresh sarcoma specimens, caffeine alone at 2 mM produced inhibition
of 0.0% to 48.2% (mean, 19.1%) and there was no case with positive sensitivity.
DBA/2NCr1BR F1 mice received a single iv
injection of cyclophosphamide (70, 120 or 200 mg/kg) alone or 2 hr before an ip
injection of 1,000 mg/kg of diethyldithiocarbamate. 24 hr after, survival of
bone marrow colony forming units spleen and granulocyte macrophage colony
forming cells, was determined. On the whole, administration of
diethyldithiocarbamate reduced the toxic effect of cyclophosphamide on
hemopoietic progenitors. The effect was in general more evident at the lower
than at the higher doses of the antitumor drug.
Leukopenic and/or thrombocytopenic effects of
cyclophosphamide may be increased with concurrent use or recent therapy if these
medications /blood dyscrasia-causing medications/ cause the same effects; dosage
adjustment of cyclophosphamide, if necessary, should be based on blood counts.
Additive bone marrow depression may occur;
dosage reduction may be required when two or more bone marrow depressants,
including radiation, are used concurrently or consecutively /with
cyclophosphamide/.
Cyclophosphamide may raise the concentration
of blood uric acid; dosage adjustment of antigout agents /allopurinol or
colchicine or probenecid or sulfinpyrazone/ my be necessary to control
hyperuricemia and gout; uricosuric antigout agents may increase risk of uric
acid nephropathy. Concurrent use with allopurinol may enhance the bone marrow
toxicity of cyclophosphamide; if concurrent use is required, close observation
of toxic effects should be considered.
Inhibition of cholinesterase activity by
cyclophosphamide reduces or slows cocaine metabolism, thereby increasing and/or
prolonging its effects and increasing the risk of toxicity.
Concurrent use of high-dose cytarabine with
cyclophosphamide for bone marrow transplant preparation has bee reported to
result in an increase in cardiomyopathy with subsequent death.
Concurrent use /of daunorubicin or doxorubicin/
with cyclophosphamide may result in increased cardiotoxicity; it is recommended
that the total dose of daunorubicin or doxorubicin not exceed 400 mg/sq m of
body surface.
These agents /hepatic enzyme inducers/ may
induce microsomal metabolism to increase formation of alkylating metabolites of
cyclophosphamide, thereby reducing the half-life and increasing the activity of
cyclophosphamide.
Concurrent use of other immunosuppressants
such as: azathioprine; chlorambucil; corticosteroids, glucocorticoid;
cyclosporine; mercaptopurine; muromonab-CD3/ with cyclophosphamide may increase
the risk of infection and development of neoplasms.
Concurrent use /of lovastatin with
cyclophosphamide/ in cardiac transplant patients may be associated with an
increased risk of rhabdomyolysis and acute renal failure.
Cyclophosphamide may decrease plasma
concentrations or activity of pseudocholinesterase, the enzyme that metabolizes
succinylcholine, thereby enhancing the neuromuscular blockage of succinylcholine.
Increased or prolonged respiratory depression or paralysis (apnea) may occur but
is of minor clinical significance while the patient is being mechanically
ventilated; however, caution and careful monitoring of the patient are
recommended during and following concurrent or sequential use, especially if
there is a possibility of incomplete reversal of neuromuscular blockage
postoperatively.
The effect of high molecular
carboxymethyl-chitin-glucan (CMCG), admin either ip, iv or orally prior to
cyclophosphamide injection, on the frequency of micronucleated reticulocytes was
evaluated in peripheral blood of female ICR mice. Both ip and iv admin of CMCG
decreased the clastogenic effect of cyclophosphamide. The protective effect of
CMCG was concn dependent, with a higher decrease achieved by 100 mg/kg than by
50 mg/kg body weight. On the other hand, no even five peroral pretreatments with
CMCG in the dose of 200 mg/kg body weight during the week prior to simultaneous
admin of CMCG and cyclophosphamide induced a decrease of micronucleated
reticulocytes in peripheral blood.
Synergistically enhanced sister chromatid
exchange (SCE) frequency by cyclophosphamide (CP) was observed when L1210
lymphoid tumor cells were exposed in vivo to a non-toxic concn of
3-aminobenzamide (3-AB). Additive effects in SCE induction in vivo were observed
when either Ehrlich ascites tumor (EAT) cells or P388 lymphocytic leukemia cells
treated with CP were exposed to 3-AB in vivo. 3-AB enhanced the survival time of
L1210 tumor bearing BDF1 mice treated with CP. However, the combined CP plus
3-AB treatment did not increase the survival of either EAT BALB/c- or P388
BDF1-tumor bearing mice compared with the effect on survival by CP alone.
Therefore the in vivo differential antitumor effect, by CP in conjunction with
3-AB, appears to correlated well with the in vivo differential effect on
cytogenetic damage caused by the combined CP plus 3-AB treatment. In the
Salmonella typhimurium/mammalian microsome test CP appears to have a dose
dependent ability to induce base-pair substitutions in strains TA 100 and TA
1535 and frameshift mutations in strains TA 98 and TA 1537. Both types of
mutation were synergistically increased in the presence of 3-AB.
Treatment with Caralluma tuberculata extract
induced complex biochemical and cytological changes in mice. Its cytotoxicity in
the bone marrow cells of mice was comparable with that of the standard drug
cyclophosphamide (C); however, unlike C, C. tuberculata was not clastogenic (as
shown by the micronucleus assay). A dose-dependent decrease in the RNA content
of liver and testes was produced by C. tuberculata treatment whereas there was
no effect on the content of nucleic acid and protein in the brain. In the
extract-treated animals there was a significant and dose-dependent increase in
the DNA content of the liver, with a negligible effect on the protein content.
Combined treatment with C. tuberculata and C showed that C. tuberculata
diminished the effect of C on DNA levels; however, RNA levels were further
suppressed, resulting in increased cytotoxicity. Pretreatment with C.
tuberculata extract significantly reduced the clastogenicity of C. These results
indicated the involvement of different phytoconstituents acting by different
routes.
The effect of pretreatment with
carboxymethylglucan (CMG) on the frequency of micronuclei induced by
cyclophosphamide administration in mice was evaluated. Two doses of CMG (50
mg/kg body weight) injected either intraperitoneally 24 hr or intravenously 1 hr
prior to two cyclophosphamide administrations (80 mg/kg) significantly decreased
the frequency of micronucleated PCE in bone marrow. Of two evaluated derivatives
of carboxymethylglucan, the K3 derivative was most efficient. The results show
that it is possible to achieve a suppressive effect of soluble
carboxymethylglucan prepared from Saccharomyces cerevisiae against
cyclophosphamide mutagenicity. The notion may be useful for glucan's effects
against pharmacocarcinogenesis. Therapeutic application of glucan with
cyclophosphamide therapy may provide a remarkable decrease of the secondary
tumor risk. The utilization of these results for human patients needs to be
considered.
The modulatory effect of vitamin C (Vit C) on
the mutagenic effect of the antineoplastic drug cyclophosphamide (CP) was
assessed in the in vivo micronucleus test in Swiss mice. Simultaneous oral
administration of Vit C with ip administration of CP was found to decrease the
frequency of micronucleated polychromatic erythrocytes elevated by CP. Vit C
exhibited a significant antimutagenic effect over a wide dose range (1.56-200
mg/kg). The dose-response relationship was highly significant. These results
demonstrated the ability of the in vivo micronucleus test to detect in vivo
modulation of CP mutagenicity by Vit C. Our earlier results and those from other
laboratories also indicate that this model system is suitable for primary in
vivo screening of modulation of mutagenesis.
A total of 78 patients with second recurrence
or progression of histologically verified breast cancer were treated with
single-agent cyclophosphamide given at 2.5 g/sq m by iv infusion every 3 wk
along with mesna support. All had previously been treated with epirubicin and
cisplatin or epirubicin alone. Toxicity was predominantly hematologic: WHO grade
III+IV toxicity was found in 95% of cases. The overall response rate was 26.7%
(95% CI, 15.8-41.4%), with 7% of patients achieving a complete response (CR) and
19.7%, a partial response (PR). The median duration of CRs and PRs was 11 and 5
mo, respectively. The response rate observed for patients previously treated
with epirubicin alone was 30.5% in contrast to the 8.3% recorded for patients
previously treated with cisplatin plus epirubicin. Thus, an indication of
cross-resistance was absent between cyclophosphamide and epirubicin but possible
between cyclophosphamide and cisplatin.
The effect of WR-2721 against
cyclophosphamide-induced clastogenicity was studied using the in vivo
micronucleus assay. The frequency of micronuclei in polychromatic erythrocytes
in the peripheral blood of mice treated with WR-2721 and cyclophosphamide (CP),
each of the cmpd at a dose of 200 mg/kg body weight, was evaluated during the
15-day period. The suppressing effect of WR-2721, given 30 min prior to CP
admin, on micronuclei induced by the alkylating agent was demonstrated ... The
modulatory effect of WR-2721 on the clastogenic activity of CP in the
erythropoietic system by the mouse micronucleus test was shown.
/It was/ ... demonstrated in an earlier paper
that capsaicin, the pungent principle of red hot chili, has a potent
anti-oxidant property that interferes with free-radical involved mechanisms. In
the present paper we demonstrate that capsaicin significantly inhibits
cyclophosphamide-induced (ip) chromosomal aberrations and DNA strand breakages.
This protective action of capsaicin against CP-induced toxicity may possibly be
linked with its already reported 'desensitization' effect against chemical
irritant-induced damages.
In the rat, the mortality from
cyclophosphamide had prevented the administration of sufficient dosages to
produce detectible damage to stem spermatogonia. To overcome this problem, we
used bone marrow transplantation and sodium 2-mercaptoethanesulfonate (Mesna)
treatment to raise the lethal dose for 50% of the animals (LD50) for
cyclophosphamide from 275 to > 400 mg/kg body weight. In addition we used
irradiation, 2 weeks prior to injection of cyclophosphamide, to greatly enhance
the measured toxicity of cyclophosphamide towards stem spermatogonia. Whereas
sperm counts at 9 weeks after a 300 mg/kg cyclophosphamide dose were reduced by
only a factor of 1.6 without prior irradiation, they were reduced by a factor of
60 when 2.5 Gy of irradiation had been given. Dramatic protection against this
toxicity was produced by hormone treatment with a gonadotropin-releasing hormone
(GnRH) antagonist (Nal-Glu) and an antiandrogen (flutamide) following the
radiation but prior to cyclophosphamide. This hormone treatment did not modify
the stem cell toxicity of the radiation and it therefore must be protecting stem
cells against cyclophosphamide-induced damage.
Hamster to rat renal xenotransplantation was
performed with recipient nephrectomies. Recipients were treated beginning on day
0 with continuous FK 506 monotherapy, a 7-day or open-ended monotherapeutic
course of cyclophosphamide (CP), and the two drug regiments combined. CP alone
(10 mg/kg/day) prevented a xenospecific antibody response and tripled median
survival of the kidney (defined as recipient death) from 6 (control) to 18.5
days whereas FK 506 alone had no effect. The drugs in combination were no better
than CP alone (15 days) unless the 5-day course of CP was given at a higher dose
(15 mg/kg) and started 3 days preoperatively (79 days). In further experiments,
adjuvant measures were added to the minimally effective FK 506/7-day CP regimen
which gave a median survival of only 15 days. In the most successful
modification, intraoperative antibody depletion by the temporary transplantation
of third party hamster liver or en bloc kidneys increased median survival from
15 to 34 and 48 days, respectively. An intraoperative i.v. dose administration
of the anticomplement drug K76 instead of antibody depletion increased survival
to 26 days. Although the events of kidney rejection were similar to those of
heart xenografts and partially forestalled by the antibody inhibiting CP
treatment, or by antibody depletion, survival for > 100 days was accomplished
in only 5 of 86 treated animals.
Hemorrhagic cystitis is a common problem
following cyclophosphamide or radiation therapy. Chitosan has been shown to be
an effective hemostatic agent and promoter of wound healing in animal
experiments. We evaluated the safety and efficacy of intravesical chitosan in an
animal model of cyclophosphamide cystitis. Hemorrhagic cystitis was induced in
female F344 rats by intraperitoneal cyclophosphamide, 100 mg/kg Chitosan soln
(0.3 ml) was instilled intravesically on day 1 (Group 1), on days 1, 3, and 5
(Group 2), or 1 hr after the admin of cyclophosphamide (Group 3). The rats in
group 4 were treated with chitosan diluent on day 1 after cyclophosphamide, and
the rats in group 5 received intravesical chitosan without cyclophosphamide.
Sequential examination revealed decr mortality and lower incidences of severe
bladder bleeding, necrosis and inflammation in Group 3. Treatment delayed until
after the appearance of the cystitis, esp repeated treatments, appeared to make
the cyclophosphamide-induced changes worse. Used within 1 hr of cyclophosphamide
admin, before the cystitis develops, chitosan seemed to have the possibility to
inhibit the appearance of hemorrhagic cystitis. In addition to the changes in
the bladder, severe changes occurred in the kidneys secondary to
cyclophosphamide.
The effect of pretreatment with miltefosine
(MIL) on the antineoplastic activity of cyclophosphamide (CPA) was evaluated in
sc benzo(a)pyrene-induced sarcomas (BPS) of the rat. MIL alone had no
antineoplastic effect on this autochthonous tumor, but enhanced the
chemotherapeutic effect of CPA. Conversely, MIL counteracted the myelotoxicity
of CPA in normal adult rats. Although the nadir of the leucocyte count remained
unchanged, the recovery phase was considerably shortened, an effect which
resembled the pharmacological action of GM-CSF.
The effect of protein malnutrition and alcohol
consumption on the yield of chromosomal damage induced by cyclophosphamide (CP)
was studied. Chromosomal damage induced in bone marrow cells of BALB/c mice was
established by scoring the frequency of dicentric chromosomes in C-banded
slides. Results obtained showed that CP induced a significant incr of
chromosomal damage in comparison with untreated mice. In addition, the yield of
dicentric chromosomes was higher in mice fed with the hypoproteic diet. The
animals which received ethanol in drinking water before treatment with CP
exhibited the highest frequency of dicentric chromosomes, with no relation with
the diet.
Cyclophosphamide causes lung injury in rats
through its ability to generate free radicals with subsequent endothelial and
epithelial cell damage. In order to observe the protective effects of a potent
anti-inflammatory antioxidant, curcumin (diferuloyl methane) on
cyclophosphamide-induced early lung injury, healthy, pathogen free male Wistar
rats were exposed to 20 mg/100 g body weight of cyclophosphamide,
intraperitoneally as a single injection. Prior to cyclophosphamide intoxication
oral administration of curcumin was performed daily for 7 days. At various time
intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed
for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and
ascorbic acid Bronchoalveolar lavage fluid was analyzed for biochemical
constituents. The lavage cells were examined for lipid peroxidation and
glutathione content. Excised lungs were analyzed for antioxidant enzyme levels.
Biochemical analyses revealed time course increases in lavage fluid total
protein, albumin, angio+ensin converting enzyme (ACE), lactate dehydrogenase,
N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid
peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2,
3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid
peroxidation and decreased levels of glutathione and ascorbic acid were seen in
serum, lung tissue and lavage cells of cyclophosphamide groups. Serum
angiotensin converting enzyme activity increased which coincided with the
decrease in lung tissue levels. Activities of antioxidant enzymes were reduced
with time in the lungs of cyclophosphamide groups.
Maximum Drug Dose:
A total of 23 patients were treated at five
dose escalations with high dose combination cyclophosphamide, cis-platin, and
melphalan with autologous bone marrow support. The max tolerated doses of
cyclophosphamide, cis-platin, and melphalan were 5,525, 180, and 80 mg/sq m,
respectively. The dose limiting toxicity was cardiac toxicity. Objective tumor
regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5
mo.
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Cyclophosphamide's production and use as
antineoplastic may result in its release to the environment through various
waste streams. If released to air, an estimated vapor pressure of 4.5 mm Hg at
25 deg C indicates cyclophosphamide will exist in both the vapor and particulate
phases in the ambient atmosphere. Vapor-phase cyclophosphamide will be degraded
in the atmosphere by reaction with photochemically-produced hydroxyl radicals;
the half-life for this reaction in air is estimated to be 5.5 hrs.
Particulate-phase cyclophosphamide will be removed from the atmosphere by wet
and dry deposition. Cyclophosphamide is sensitive to light. If released to soil,
cyclophosphamide is expected to have high mobility based upon an estimated Koc
of 52. Volatilization from moist soil surfaces is not expected to be an
important fate process based upon an estimated Henry's Law constant of 1.4X10-11
atm-cu m/mole. Cyclophosphamide has shown to be non-biodegradable using sewage
sludge tests. If released into water, cyclophosphamide is not expected to adsorb
to suspended solids and sediment based upon the estimated Koc. Volatilization
from water surfaces is not expected to be an important fate process based upon
this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests
the potential for bioconcentration in aquatic organisms is low. The neutral
hydrolysis calculated half-life for cyclophosphamide at 25 deg C is 41 days.
Occupational exposure to cyclophosphamide may occur through inhalation and
dermal contact with this compound at workplaces where cyclophosphamide is
produced or used. Workers involved in formulating and dispensing the drug may be
exposed through dermal contact (with the dry powder or solutions), or inhalation
of dust. Direct human exposure occurs through ingestion of the drug (when
dispensed in tablet form) and through injection (when administered
intravenously). (SRC)
Probable Routes of Human Exposure:
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
danger to health-care personnel from handling a hazardous drug stems from a
combination of its inherent toxicity and the extent to which workers are exposed
to the drug in the course of carrying out their duties. This exposure may be
through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches),
inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic
agents/
NIOSH (NOES Survey 1981-1983) has
statistically estimated that 30,026 workers (20,745 of these are female) are
potentially exposed to cyclophosphamide in the US(1). Occupational exposure to
cyclophosphamide may occur through inhalation and dermal contact with this
compound at workplaces where cyclophosphamide is produced or used(SRC). Workers
involved in formulating and dispensing the drug may be exposed through dermal
contact (with the dry powder or solutions), or inhalation of dust(SRC). Direct
human exposure occurs through ingestion of the drug (when dispensed in tablet
form) and through injection (when administered intravenously)(2).
Air monitoring conducted in a West German
manufacturing facility in April 1984 found cyclophosphamide levels ranging from
0.1 to 810 ug/cu m(1). Air concentrations of 2-480 ug/cu m were detected in a
production area of a plant involved weighing cyclophosphamide and formulating it
into tablets(1). No detectable levels (detection limit of 0.05 ug/cu m) were
found in air samples (taken from flow hoods) from a hospital dispensing and
administering cyclophosphamide; however, filter media from the flow hoods
contained measurable quantities suggesting that some exposure can occur(1).
Concentrations of cyclophosphamide in personal air samplers from a manufacturing
facility ranged from less than the detection limit to 97.0 ug/cu m, and in a
laminar-flow hood, the concentrations ranged from 0-60 ng/cu m(2).
Body Burden:
In a cross-sectional study, the urine of 20
hospital workers occupationally exposed to cyclophosphamide and 21 unexposed
controls was monitored for excretion of cyclophosphamide. During the week in
which samples were collected, most of the workers handled cyclophosphamide fewer
than 5 times and the amount handled each time ranged from 100-1000 mg (mean +/-
350 mg). All workers claimed to have taken regular safety precautions, ie, at
least wearing gloves during handling. The drug was identified in 5 cases (range:
0.7-2.5 ug excreted/24 hr urine). A clear relationship between cyclophosphamide
handling and urinary detection was shown. 4 of 5 persons with detectable urinary
cyclophosphamide had handled cyclophosphamide 10 times or more during the week.
Cyclophosphamide (along with ifosfamide) was
detected in the urine of 8 pharmacy technicians and nurses (along with
ifosfamide) at amounts ranging from <0.001-0.5 ug(1). 21 nurses and pharmacy
personnel in a Munich, Germany hospital were monitored for compound exposure; on
days when 3,900 mg/l cyclophosphamide was mixed, 12 of 31 urine samples tested
positive with concentrations ranging from 3.5 to 38 ug/24 hr urine(2).
Natural Pollution Sources:
Cyclophosphamide is not known to occur in
nature(1).
Artificial Pollution Sources:
Cyclophosphamide's production and use as an
antineoplastic(1) may result in its release to the environment through various
waste streams(SRC).
Environmental Fate:
TERRESTRIAL FATE: Based on a classification
scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of
0.63(2) and a regression-derived equation(3), indicates that cyclophosphamide is
expected to have high mobility in soil(SRC). Volatilization of cyclophosphamide
from moist soil surfaces is not expected to be an important fate process(SRC)
given an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), using a
fragment constant estimation method(4). Cyclophosphamide is not expected to
volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of
4.4X10-5 mm Hg(SRC), determined from a fragment constant method(5).
Cyclophosphamide has been shown to be non-biodegradable using laboratory-scale
sewage treatment studies(6), suggesting that biodegradation in soil may be
slow(SRC).
AQUATIC FATE: Based on a classification
scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of
0.63(2) and a regression-derived equation(3), indicates that cyclophosphamide is
not expected to adsorb to suspended solids and sediment(SRC). Volatilization
from water surfaces is not expected(3) based upon an estimated Henry's Law
constant of 1.4X10-11 atm-cu m/mole(SRC), developed using a fragment constant
estimation method(4). The neutral hydrolysis calculated half-life for
cyclophosphamide at 25 deg C is 41 days(5). According to a classification
scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a
regression-derived equation(7), suggests the potential for bioconcentration in
aquatic organisms is low(SRC). Cyclophosphamide has been shown to be
non-biodegradable using laboratory-scale sewage treatment studies(8).
ATMOSPHERIC FATE: According to a model of
gas/particle partitioning of semivolatile organic compounds in the
atmosphere(1), cyclophosphamide, which has an estimated vapor pressure of
4.4X10-5 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2),
will exist in both the vapor and particulate phases in the ambient atmosphere.
Vapor-phase cyclophosphamide is degraded in the atmosphere by reaction with
photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction
in air is estimated to be 5.5 hrs(SRC), calculated from its rate constant of
7.0X10-11 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure
estimation method(3). Particulate-phase cyclophosphamide may be removed from the
air by wet and dry deposition(SRC). Cyclophosphamide is susceptible to light(4)
and therefore the potential for direct photolysis exists(SRC).
Environmental Biodegradation:
AEROBIC: Cyclophosphamide has been shown to be
non-biodegradable in a laboratory-scale sewage treatment studies(1-3). During 29
days of 10 ug/l compound addition, a mean effluent recovery of 83% was
established(2). Cyclophosphamide, present at 160 mg/l, indicated no DOC
elimination in four weeks using an activated sludge inoculum at 0.2 g/l and the
Zahn-Wellens test(2). The compound is confirmed to be non-biodegradable
according to the OECD confirmatory test using both single compound and compound
mixtures run from a period of 10-14 days at concentrations ranging from 150 to
750 mg/l and that employs a sewage sludge inoculum(3).
Environmental Abiotic Degradation:
The rate constant for the vapor-phase reaction
of cyclophosphamide with photochemically-produced hydroxyl radicals has been
estimated as 7.0X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure
estimation method(1). This corresponds to an atmospheric half-life of about 5.5
hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1).
Hydrolysis occurs at temperatures above 30 deg C, with removal of chlorine
atoms(2). The neutral hydrolysis rate constant for cyclophosphamide at 25 deg C
has been experimentally determined to be 7.1X10-4/hour which corresponds to a
calculated half-life of 41 days(3). Cyclophosphamide is reported to be sensitive
to oxidation, moisture, and light(4); it darkens on exposure to light(2).
Environmental Bioconcentration:
An estimated BCF of 3 was calculated for
cyclophosphamide(SRC), using a log Kow of 0.63(1) and a regression-derived
equation(2). According to a classification scheme(3), this BCF suggests the
potential for bioconcentration in aquatic organisms is low(SRC).
Soil Adsorption/Mobility:
The Koc of cyclophosphamide is estimated as
52(SRC), using a log Kow of 0.63(1) and a regression-derived equation(2).
According to a classification scheme(3), this estimated Koc value suggests that
cyclophosphamide is expected to have high mobility in soil.
Volatilization from Water/Soil:
The Henry's Law constant for cyclophosphamide
is estimated as 1.4X10-11 atm-cu m/mole(SRC) using a fragment constant
estimation method(1). This Henry's Law constant indicates that cyclophosphamide
is expected to be essentially nonvolatile from water surfaces(2).
Cyclophosphamide is not expected to volatilize from dry soil surfaces(SRC) based
upon an estimated vapor pressure of 4.5X10-5 mm Hg(SRC), determined from a
fragment constant method(3).
Effluent Concentrations:
Cyclophosphamide concentrations of 149 ng/l(1)
and 19 ng/l to 4.5 ug/l(2) were detected in hospital sewage samples from
unspecified locations.
Atmospheric Concentrations:
SOURCE DOMINATED: Air monitoring conducted in
a West German manufacturing facility in April 1984 found cyclophosphamide levels
ranging from 0.1 to 810 ug/cu m(1). Air concentrations of 2-480 ug/cu m were
detected in a production area of a plant involved weighing cyclophosphamide and
formulating it into tablets(1).
Environmental Standards & Regulations:
CERCLA Reportable Quantities:
Persons in charge of vessels or facilities are
required to notify the National Response Center (NRC) immediately, when there is
a release of this designated hazardous substance, in an amount equal to or
greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number
of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202)
426-2675. The rule for determining when notification is required is stated in 40
CFR 302.4 (section IV. D.3.b).
RCRA Requirements:
U058; As stipulated in 40 CFR 261.33, when
cyclophosphamide, as a commercial chemical product or manufacturing chemical
intermediate or an off-specification commercial chemical product or a
manufacturing chemical intermediate, becomes a waste, it must be managed
according to Federal and/or State hazardous waste regulations. Also defined as a
hazardous waste is any residue, contaminated soil, water, or other debris
resulting from the cleanup of a spill, into water or on dry land, of this waste.
Generators of small quantities of this waste may qualify for partial exclusion
from hazardous waste regulations (40 CFR 261.5).
FDA Requirements:
Manufacturers, packers, and distributors of
drug and drug products for human use are responsible for complying with the
labeling, certification, and usage requirements as prescribed by the Federal
Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq.,
as amended; 21 U.S.C. 321-392).
Chemical/Physical Properties:
Molecular Formula:
C7-H15-Cl2-N2-O2-P
Molecular Weight:
261.10
Color/Form:
LIQUEFIES ON LOSS OF ITS WATER OF
CRYSTALLIZATION
Crystalline solid
Odor:
Odorless
Taste:
Slightly bitter
Melting Point:
49.5-53 deg C
Octanol/Water Partition Coefficient:
log Kow = 0.63
Solubilities:
1 in 25 parts water
1 in 1 parts alcohol
Slightly soluble in benzene, carbon
tetrachloride; very slightly soluble in ether and acetone
Soluble in chloroform, dioxane and glycols and
insoluble in carbon tetrachloride and carbon disulfide.
In water, 40,000 ppm @ 20 deg C
Spectral Properties:
Intense mass spectral peaks: 69 m/z, 147 m/z,
175 m/z, 211 m/z, 260 m/z
Other Chemical/Physical Properties:
Fine, white, crystalline powder; odorless or
almost odorless; slightly bitter taste /Monohydrate/
MP: 41-45 deg C; MW: 279.10. Solubility: 40
g/l in water; slightly sol in alcohol, benzene, ethylene glycol, dioxane, carbon
tetrachloride; sparingly sol in ether and acetone /Monohydrate/
Darkens on exposure to light. Hydrolysis
occurs at temperatures above 30 deg C, with removal of chlorine atoms.
Sensitive to oxidation, moisture, and light.
Chemical Safety & Handling:
Hazards Summary:
The major hazards encountered in the use and
handling of cyclophosphamide stem from its toxicologic properties. Exposure to
this odorless, white, crystalline powder may occur from its manufacture,
formulation, or distribution for use as an antineoplastic drug. Effects from
exposure may include fever, chills, shortness of breath, dizziness, fatigue,
headache, nausea, hemorrhagic colitis, hepatitis, leukopenia, and pneumonitis or
interstitial pulmonary fibrosis. Cyclophosphamide has been indicated as a human
carcinogen (Group 1) by the International Agency for Research on Cancer (IARC).
Exposure should be controlled by mechanical ventilation with high-efficiency
particulate arrestors (HEPA) or charcoal filters to minimize the amount of the
substance in exhausted air. In activities or situations where over-exposure may
occur, wear protective clothing and a carefully fitted respirator. Potentially
exposed skin should be thoroughly washed with soap and water. Contaminated
clothing should be removed and discarded or left at the work site for cleaning
before reuse. Smoking, eating, and drinking should be prohibited in
cyclophosphamide work areas. Cyclophosphamide should be stored and transported
in securely sealed glass bottles or ampoules, which are in turn placed inside
strong screw-cap or snap-top containers. Also, the material should be stored
cool (below 30 deg C), dry, and shielded from light. This substance is a good
candidate for disposal by rotary kiln, or fluidized bed forms of incineration.
Skin, Eye and Respiratory Irritations:
A powerful skin irritant.
Hazardous Reactivities & Incompatibilities:
/It was/ reported that immersion of a needle
with an aluminum component in cyclophosphamide 20 mg/ml resulted in a slight
darkening of the aluminum & gas production after a few days at 24 deg C with
protection from light.
Hazardous Decomposition:
When heated to decomposition it emits highly
toxic fumes of /phosphorus oxides, nitrogen oxides, & hydrogen chloride/.
The rate constant for decomp of
cyclophosphamide when constituted with benzyl alcohol-preserved bacteriostatic
water for injection is significantly higher than with sterile water for
injection. It was suggested that benzyl alcohol may catalyze somewhat the decomp
of cyclophosphamide the rate of decomp is independent of pH over the range of
2-10.
Protective Equipment & Clothing:
PRECAUTIONS FOR "CARCINOGENS": ...
Dispensers of liq detergent /should be available./ ... Safety pipettes should be
used for all pipetting. ... In animal laboratory, personnel should ... wear
protective suits (preferably disposable, one piece & close fitting at ankles
& wrists), gloves, hair covering & overshoes. ... In chemical
laboratory, gloves & gowns should always be worn ... however, gloves should
not be assumed to provide full protection. Carefully fitted masks or respirators
may be necessary when working with particulates or gases, & disposable
plastic aprons might provide addnl protection. ... gowns ... /should be/ of
distinctive color, this is a reminder that they are not to be worn outside the
laboratory. /Chemical Carcinogens/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Protective apparel: Disposable closed-front gown or coveralls, disposable
utility gloves over disposable latex gloves, NIOSH-approved air-purifying
half-mask respirator equipped with a high efficiency filter, and eye protection
should be worn. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class
100 clean-air work stations, both horizontal and vertical airflow (with no
containment characteristics), are inappropriate engineering controls for
handling hazardous drugs because they provide no personnel protection and permit
environmental contamination. Although there are no engineering controls designed
specifically for the safe handling of hazardous chemicals as sterile products,
Class II contained vertical-flow biological safety cabinets (biohazard cabinets)
have been adopted for this use. Biohazard cabinetry is, however, designed for
the handling of infectious agents, not hazardous chemicals. ... Based on design,
ease of use, and cost considerations, Class II contained-vertical-flow biohazard
cabinetry is currently recommended for use in preparing sterile doses of
hazardous drugs. Class II cabinetry design and performance specifications are
defined in NSF Standard 49. Biological safety cabinets selected for use with
hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum
protection from these engineering controls. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Workers should wear powder free, disposable surgical latex gloves of good
quality when preparing hazardous drugs. Selection criteria for gloves should
include thickness (especially at the fingertips where stress is the greatest),
fit, length, and tactile sensation. ... The practice of double gloving is
supported by research that indicates that many glove materials vary in drug
permeability even within lots; therefore, double gloving is recommended. ... In
general, surgical latex gloves fit better, have appropriate elasticity for
double gloving and maintaining the integrity of the glove-gown interface, and
have sufficient tactile sensation (even during double gloving) for stringent
aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Workers who are not protected by the containment environment of a biohazard
cabinet should use respiratory protection when handling hazardous drugs.
Respiratory protection should be an adjunct to and not a substitute for
engineering controls. Surgical masks of all types provide no respiratory
protection against powdered or liquid aerosols of hazardous drugs. In situations
where workers may be exposed to potential eye contact with hazardous drugs, an
appropriate plastic face shield or splash goggles should be worn. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
During compounding of hazardous drugs (eg, crushing, dissolving, and preparing
an ointment), workers should wear low permeability gowns and double gloves.
Compounding should take place in a protective area such as a disposable glove
box. If compounding must be done in the open, an area away from drafts and
traffic must be selected, and the worker should use appropriate respiratory
protection. /Antineoplastic agents/
Preventive Measures:
PRECAUTIONS FOR "CARCINOGENS":
Smoking, drinking, eating, storage of food or of food & beverage containers
or utensils, & the application of cosmetics should be prohibited in any
laboratory. All personnel should remove gloves, if worn, after completion of
procedures in which carcinogens have been used. They should ... wash ... hands,
preferably using dispensers of liq detergent, & rinse ... thoroughly.
Consideration should be given to appropriate methods for cleaning the skin,
depending on nature of the contaminant. No standard procedure can be
recommended, but the use of organic solvents should be avoided. Safety pipettes
should be used for all pipetting. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": In
animal laboratory, personnel should remove their outdoor clothes & wear
protective suits (preferably disposable, one piece & close fitting at ankles
& wrists), gloves, hair covering & overshoes. ... clothing should be
changed daily but ... discarded immediately if obvious contamination occurs ...
/also,/ workers should shower immediately. In chemical laboratory, gloves &
gowns should always be worn ... however, gloves should not be assumed to provide
full protection. Carefully fitted masks or respirators may be necessary when
working with particulates or gases, & disposable plastic aprons might
provide addnl protection. If gowns are of distinctive color, this is a reminder
that they should not be worn outside of lab. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": ...
Operations connected with synth & purification ... should be carried out
under well ventilated hood. Analytical procedures ... should be carried out with
care & vapors evolved during ... procedures should be removed. ... Expert
advice should be obtained before existing fume cupboards are used ... & when
new fume cupboards are installed. It is desirable that there be means for
decreasing the rate of air extraction, so that carcinogenic powders can be
handled without ... powder being blown around the hood. Glove boxes should be
kept under negative air pressure. Air changes should be adequate, so that concn
of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS":
Vertical laminar flow biological safety cabinets may be used for containment of
in vitro procedures ... provided that the exhaust air flow is sufficient to
provide an inward air flow at the face opening of the cabinet, &
contaminated air plenums that are under positive pressure are leak tight.
Horizontal laminar flow hoods or safety cabinets, where filtered air is blown
across the working area towards the operator, should never be used ... Each
cabinet or fume cupboard to be used ... should be tested before work is begun (eg,
with fume bomb) & label fixed to it, giving date of test & avg air flow
measured. This test should be repeated periodically & after any structural
changes. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS":
Principles that apply to chem or biochem lab also apply to microbiological &
cell culture labs ... Special consideration should be given to route of admin.
... Safest method of administering volatile carcinogen is by injection of a soln.
Admin by topical application, gavage, or intratracheal instillation should be
performed under hood. If chem will be exhaled, animals should be kept under hood
during this period. Inhalation exposure requires special equipment. ... unless
specifically required, routes of admin other than in the diet should be used.
Mixing of carcinogen in diet should be carried out in sealed mixers under fume
hood, from which the exhaust is fitted with an efficient particulate filter.
Techniques for cleaning mixer & hood should be devised before expt begun.
When mixing diets, special protective clothing &, possibly, respirators may
be required. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": When
... admin in diet or applied to skin, animals should be kept in cages with solid
bottoms & sides & fitted with a filter top. When volatile carcinogens
are given, filter tops should not be used. Cages which have been used to house
animals that received carcinogens should be decontaminated. Cage cleaning
facilities should be installed in area in which carcinogens are being used, to
avoid moving of ... contaminated /cages/. It is difficult to ensure that cages
are decontaminated, & monitoring methods are necessary. Situations may exist
in which the use of disposable cages should be recommended, depending on type
& amt of carcinogen & efficiency with which it can be removed. /Chemical
Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": To
eliminate risk that ... contamination in lab could build up during conduct of
expt, periodic checks should be carried out on lab atmospheres, surfaces, such
as walls, floors & benches, & ... interior of fume hoods & airducts.
As well as regular monitoring, check must be carried out after cleaning up of
spillage. Sensitive methods are required when testing lab atmospheres. ...
Methods ... should ... where possible, be simple & sensitive. ... /Chemical
Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Rooms
in which obvious contamination has occurred, such as spillage, should be
decontaminated by lab personnel engaged in expt. Design of expt should ... avoid
contamination of permanent equipment. ... Procedures should ensure that
maintenance workers are not exposed to carcinogens. ... Particular care should
be taken to avoid contamination of drains or ventilation ducts. In cleaning
labs, procedures should be used which do not produce aerosols or dispersal of
dust, ie, wet mop or vacuum cleaner equipped with high efficiency particulate
filter on exhaust, which are avail commercially, should be used. Sweeping,
brushing & use of dry dusters or mops should be prohibited. Grossly
contaminated cleaning materials should not be reused ... If gowns or towels are
contaminated, they should not be sent to laundry, but ... decontaminated or
burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": Doors
leading into areas where carcinogens are used ... should be marked distinctively
with appropriate labels. Access ... limited to persons involved in expt. ... A
prominently displayed notice should give the name of the Scientific Investigator
or other person who can advise in an emergency & who can inform others (such
as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/
SRP: Contaminated protective clothing should
be segregated in such a manner so that there is no direct personal contact by
personnel who handle, dispose, or clean the clothing. Quality assurance to
ascertain the completeness of the cleaning procedures should be implemented
before the decontaminated protective clothing is returned for reuse by the
workers. Contaminated clothing should not be taken home at end of shift, but
should remain at employee's place of work for cleaning.
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Accidental contamination of the health-care environment, resulting in exposure
of personnel, patients, visitors, and family members to hazardous substances, is
prevented by maintaining the physical integrity and security of packages of
hazardous drugs. 1. Access to all areas where hazardous drugs are stored is
limited to specified authorized staff. 2. A method should be present for
identifying to personnel those drugs that require special precautions (eg,
cytotoxics). One way to accomplish this is to apply appropriate warning labels
to all hazardous drug containers, shelves, and bins where the drug products are
stored. ... 3. A method of identifying, for patients and family members, those
drugs that require special precautions in the home should be in place. This may
be accomplished in the health-care setting, by providing specific labeling for
discharge medications, along with written instructions. 4. Methods for
identifying shipping cartons of hazardous drugs should be required from
manufacturers and distributors of these drugs. 5. Written procedures for
handling damaged packages of hazardous drugs should be maintained. Personnel
involved in shipping and receiving hazardous drugs should be trained in these
procedures, including the proper use of protective garments and equipment.
Damaged shipping cartons of hazardous drugs should be received and opened in an
isolated area (eg, in a laboratory fume hood, if available, not in a vertical
laminar airflow biological safety cabinet used for preparing sterile products).
/Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs
are designed to prevent breakage and to limit contamination in the event of
leakage. Bins, shelves with barriers at the front, or other design features that
reduce the chance of drug containers falling to the floor should be used.
Hazardous drugs requiring refrigeration should be stored separately from
nonhazardous drugs in individual bins designed to prevent breakage and to
contain leakage. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until
the reproductive risks (or lack thereof) associated with handling hazardous
drugs within a safety program have been substantiated, staff who are pregnant or
breast-feeding should be allowed to avoid contact with these drugs. Policies
should be in effect that provide these individuals with alternative tasks or
responsibilities if they so desire. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
pharmacy should provide access to information on toxicity, treatment of acute
exposure (if available), chemical inactivators, solubility and stability of
hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Appropriate engineering controls should be in place to protect the drug product
from microbial contamination and to protect personnel and the environment from
the potential hazards of the product. These engineering controls should be
maintained according to applicable regulations and standards. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Biological safety cabinets should be cleaned and disinfected regularly to ensure
a proper environment for preparation of sterile products. For routine cleanups
of surfaces between decontaminations, water should be used (for injection or
irrigation) with or without a small amount of cleaner. If the contamination is
soluble only in alcohol, then 70% isopropyl or ethyl alcohol may be used in
addition to the cleaner. In general, alcohol is not a good cleaner, only a
disinfectant, and its use in a biohazard cabinet should be limited. The
biohazard cabinet should be disinfected with 70% alcohol before any aseptic
manipulation is begun. The excessive use of alcohol should be avoided in
biohazard cabinets where air is recirculated ... because alcohol vapors may
build up in the cabinet. A lint-free, plastic-backed disposable liner may be
used in the biological safety cabinet to facilitate spill cleanup. ... If used,
the liner should be changed frequently ... /or/ whenever it is overtly
contaminated. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
biological safety cabinets should be decontaminated on a regular basis (ideally
at least weekly) and whenever there is a spill or the biological safety cabinet
is moved or serviced, including for certification. ... Currently, no single
reagent will deactivate all known hazardous drugs; therefore, decontamination of
a biological safety cabinet used for such drugs is limited to removal of
contamination from a nondisposable surface (the cabinet) to a disposable surface
(eg, gauze or towels) by use of a good cleaning agent that removes chemicals
from stainless steel. The cleaning agent selected should have a pH approximating
that of soap and be appropriate for stainless steel. Cleaners containing
chemicals such as quaternary ammonium compounds should be used with caution,
because they may be hazardous to humans and their vapors may build up in any
biological safety cabinet where air is recirculated. Similar caution should be
used with any pressurized aerosol cleaner; spraying a pressurized aerosol into a
biological safety cabinet may disrupt the protective containment airflow, damage
the high efficiency particulate air filter, and cause an accumulation of the
propellant within a biological safety cabinet where air is recirculated,
resulting in a fire and explosion hazard. During decontamination, the operator
should wear a disposable closed front gown, disposable latex gloves covered by
disposable utility gloves, safety glasses or goggles, a hair covering, and a
disposable respirator, because the glass shield of the biological safety cabinet
occasionally must be lifted. The blower must be left on, and only heavy toweling
or gauze should be used in the biological safety cabinet to prevent it from
being "sucked" up the plenum and into the high efficiency particulate
air filter. Decontamination should be done from top to bottom (areas of lesser
contamination to greater) by applying the cleaner, scrubbing, and rinsing
thoroughly with distilled or deionized water. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
high efficiency particulate air filters /or other exhaust scrubbing system/ of
the biohazard cabinet must be replaced whenever they restrict required airflow
velocity or if they are overtly contaminated (eg, by a breach in technique that
causes hazardous drug to be introduced onto the clean side of the supply high
efficiency particulate air filter). Personnel and environmental protection must
be maintained during replacement of a contaminated high efficiency particulate
air filter. Because replacement of a high efficiency particulate air filter
generally requires breaking the integrity of the containment aspect of the
cabinet, this procedure may release contamination from the filter into the
pharmacy or intravenous preparation area if carried out in an inappropriate
manner. Before replacement of a high efficiency particulate air filter
contaminated with hazardous drugs, the biological safety cabinet service agent
should be consulted for a mutually acceptable procedure for replacing and
subsequently disposing of a contaminated high efficiency particulate air filter.
One procedure would include moving the biological safety cabinet to a secluded
area or using plastic barriers to segregate the contaminated area. Protective
clothing and equipment must be used by the servicer. The biological safety
cabinet should be decontaminated before filter replacement. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
During removal of gloves, ... avoid touching the inside of the glove or the skin
with the contaminated glove fingers. ... The worker should wear a protective
disposable gown made of lint free, low-permeability fabric with a solid front,
long sleeves, and tight-fitting elastic or knit cuffs when preparing hazardous
drugs. Washable garments are immediately penetrated by liquids and therefore
provide little, if any protection. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ When
double gloving, one glove should be placed under the gown cuff and one over. The
glove-gown interface should be such that no skin on the arm or wrist is exposed.
Gloves and gowns should not be worn outside the immediate preparation area. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Eyewash fountains should be available in areas where hazardous drugs are
routinely handled. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Although noninjectable dosage forms of hazardous drugs contain varying
proportions of drug to nondrug (nonhazardous) components, there is potential for
personnel exposure and environmental contamination with the hazardous
components. Procedures should be developed to avoid the release of aerosolized
powder or liquid into the environment during manipulation of these drugs. Drugs
designated as hazardous should be labeled or otherwise identified as such to
prevent their improper handling. Tablet and capsule forms of these drugs should
not be placed in automated counting machines, which subject them to stress and
may introduce powdered contaminants into the work area. During routine handling
of hazardous drugs and contaminated equipment, workers should wear one pair of
gloves of good quality and thickness. The counting and pouring of hazardous
drugs should be done carefully, and clean equipment dedicated for use with these
drugs should be used. ... When hazardous drug tablets in unit-of-use packaging
are being crushed, the package should be placed in a small sealable plastic bag
and crushed with a spoon or pestle; caution should be used not to break the
plastic bag. Disposal of unused or unusable oral or topical dosage forms of
hazardous drugs should be performed in the same manner as for hazardous
injectable dosage forms and waste. ... Hazardous drug work areas should have a
sink (preferably with an eyewash fountain) and appropriate first aid equipment
to treat accidental skin or eye contact according to the protocol. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ A
distinctive warning label with an appropriate CAUTION statement should be
attached to all hazardous drug materials, consistent with state laws and
regulations. This would include, for example, syringes, IV containers,
containers of unit-dose tablets and liquids, prescription vials and bottles,
waste containers, and patient specimens that contain hazardous drugs. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Supplies of disposable gloves and gowns, safety glasses, disposable
plastic-backed absorbent liners, gauze pads, hazardous waste disposal bags,
hazardous drug warning labels, and puncture-resistant containers for disposal of
needles and ampuls should be conveniently located for all areas where hazardous
drugs are handled. Assembling a "hazardous drug preparation and
administration kit" is one way to furnish nursing and medical personnel
with the materials needed to reduce the risk of preparing and administering a
hazardous drug. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Prospective temporary and permanent employees who may be required to work with
hazardous drugs should be so notified and should receive adequate information
about the policies and procedures pertaining to their use. This notification
should be documented during the interview process and retained as part of the
employment record for all employees. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All
personnel involved with the transportation, preparation, administration, and
disposal of cytotoxic and hazardous substances should continually be updated on
new or revised information on safe handling of cytotoxic and hazardous
substances. Policies and procedures should be updated accordingly. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
work area should be designed to provide easy access to those items necessary to
prepare, label, and transport final products; contain all related waste; and
avoid inadvertent contamination of the work area. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Each
health-care setting should have an established first aid protocol for treating
cases of direct contact with hazardous drugs, many of which are irritating or
caustic and can cause tissue destruction. Medical care providers in each setting
should be contacted for input into this protocol. The protocol should include
immediate treatment measures and should specify the type and location of medical
follow-up and work-injury reporting. Copies of the protocol, highlighting
emergency measures, should be posted wherever hazardous drugs are routinely
handled. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Only
individuals trained to administer hazardous drugs should be allowed to perform
this function. Training programs should contain information on the therapeutic
and adverse effects of these drugs and the potential, long term health risk to
personnel handling these drugs. Each individual's knowledge and technique should
be evaluated before administration of these drugs. This should be done by
written examination and direct observation of the individual's performance. /Antineoplastic
agents/
Stability/Shelf Life:
AQ SOLN KEEPS FOR A FEW HR @ ROOM TEMP, BUT
HYDROLYSIS OCCURS ABOVE 30 DEG C, REMOVES CHLORINE ATOMS; DARKENS ON EXPOSURE TO
LIGHT /MONOHYDRATE/
SENSITIVE TO OXIDATION, MOISTURE ...
/MONOHYDRATE/
Constitute solns should be used within 24 hr
if stored at room temp or within 6 days if stored under refrigeration. When
constituted with sterile water for injection or paraben-preserved bacteriostatic
water for injection to a concn of 21 mg/ml, <1.5% cyclophosphamide
decomposition will occur within 8 hr at 24-27 deg C & within 6 days at 5 deg
C.
Shipment Methods and Regulations:
PRECAUTIONS FOR "CARCINOGENS":
Procurement ... of unduly large amt ... should be avoided. To avoid spilling,
carcinogens should be transported in securely sealed glass bottles or ampoules,
which should themselves be placed inside strong screw-cap or snap-top container
that will not open when dropped & will resist attack from the carcinogen.
Both bottle & the outside container should be appropriately labelled. ...
National post offices, railway companies, road haulage companies & airlines
have regulations governing transport of hazardous materials. These authorities
should be consulted before ... material is shipped. /Chemical Carcinogens/
PRECAUTIONS FOR "CARCINOGENS": When
no regulations exist, the following procedure must be adopted. The carcinogen
should be enclosed in a securely sealed, watertight container (primary
container), which should be enclosed in a second, unbreakable, leakproof
container that will withstand chem attack from the carcinogen (secondary
container). The space between primary & secondary container should be filled
with absorbent material, which would withstand chem attack from the carcinogen
& is sufficient to absorb the entire contents of the primary container in
the event of breakage or leakage. Each secondary container should then be
enclosed in a strong outer box. The space between the secondary container &
the outer box should be filled with an appropriate quantity of shock-absorbent
material. Sender should use fastest & most secure form of transport &
notify recipient of its departure. If parcel is not received when expected,
carrier should be informed so that immediate effort can be made to find it.
Traffic schedules should be consulted to avoid ... arrival on weekend or holiday
... /Chemical Carcinogens/
Storage Conditions:
Cyclophosphamide should be preserved in tight
containers, at a temperature between 2 & 32 deg C.
Protect from light.
PRECAUTIONS FOR "CARCINOGENS":
Storage site should be as close as practicable to lab in which carcinogens are
to be used, so that only small quantities required for ... expt need to be
carried. Carcinogens should be kept in only one section of cupboard, an
explosion proof refrigerator or freezer (depending on chemicophysical properties
...) that bears appropriate label. An inventory ... should be kept, showing
quantity of carcinogen & date it was acquired ... Facilities for dispensing
... should be contiguous to storage area. /Chemical Carcinogens/
Cleanup Methods:
PRECAUTIONS FOR "CARCINOGENS": A
high efficiency particulate arrestor (HEPA) or charcoal filters can be used to
minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab
hoods, glove boxes or animal rooms ... Filter housing that is designed so that
used filters can be transferred into plastic bag without contaminating
maintenance staff is available commercially. Filters should be placed in plastic
bags immediately after removal ... The plastic bag should be sealed immediately
... The sealed bag should be labelled properly ... Waste liquids ... should be
placed or collected in proper containers for disposal. The lid should be secured
& the bottles properly labelled. Once filled, bottles should be placed in
plastic bag, so that outer surface ... is not contaminated ... The plastic bag
should also be sealed & labelled. ... Broken glassware ... should be
decontaminated by solvent extraction, by chemical destruction, or in specially
designed incinerators. /Chemical Carcinogens/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill
kits containing all materials needed to clean up spills of hazardous drugs
should be assembled or purchased. These kits should be readily available in all
areas where hazardous drugs are routinely handled. If hazardous drugs are being
prepared or administered in a nonroutine area (home setting or unusual
patient-care area), a spill kit should be obtained by the drug handler. The kit
should include two pairs of disposable gloves (one outer pair of utility gloves
and one inner latex pair); low-permeability, disposable protective garments
(coveralls or gown and shoe covers); safety glasses or splash goggles;
respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling;
at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with
an appropriate warning label); a disposable scoop for collecting glass
fragments; and a puncture-resistant container for glass fragments. All
individuals who routinely handle hazardous drugs must be trained in proper spill
management and cleanup procedures. Spills and breakages must be cleaned up
immediately according to the following procedures. If the spill is not located
in a confined space, the spill area should be identified and other people should
be prevented from approaching and spreading the contamination. Wearing
protective apparel from the spill kit, workers should remove any broken glass
fragments and place them in the puncture-resistant container. Liquids should be
absorbed with a spill pad; powder should be removed with damp disposable gauze
pads or soft toweling. The hazardous material should be completely removed and
the area rinsed with water and then cleaned with detergent. The spill cleanup
should proceed progressively from areas of lesser to greater contamination. The
detergent should be thoroughly rinsed and removed. All contaminated materials
should be placed in the disposal bags provided and sealed and transported to a
designated containment receptacle. Spills occurring in the biohazard cabinet
should be cleaned up immediately; a spill kit should be used if the volume
exceeds 150 ml or the contents of one drug vial or ampule. If there is broken
glass, utility gloves should be worn to remove it and place it in the
puncture-resistant container located in the biohazard cabinet. The biological
safety cabinet, including the drain spillage trough, should be thoroughly
cleaned. If the spill is not easily and thoroughly contained, the biological
safety cabinet should be decontaminated after cleanup. If the spill contaminates
the high efficiency particulate air filter, use of the biological safety cabinet
should be suspended until the cabinet has been decontaminated and the high
efficiency particulate air filter replaced. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If
hazardous drugs are routinely prepared or administered in carpeted areas,
special equipment is necessary to remove the spill. Absorbent powder should be
substituted for pads or sheets and left in place on the spill for the time
recommended by the manufacturer. The powder should then be picked up with a
small vacuum unit reserved for hazardous drug cleanup. The carpet should then be
cleaned according to usual procedures. The vacuum bag should be removed and
discarded or cleaned, and the exterior of the vacuum cleaner should be washed
with detergent and rinsed before being covered and stored. The contaminated
powder should be discarded into a sealable plastic bag and segregated with other
contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units
may be purchased for this express use and used with appropriate cleaners. All
such units are contaminated, once used, and must be cleaned, stored, and
ultimately discarded /properly/ ... The circumstances and handling of spills
should be documented. Health-care personnel exposed during spill management
should also complete an incident report or exposure form. /Antineoplastic
agents/
Disposal Methods:
Generators of waste (equal to or greater than
100 kg/mo) containing this contaminant, EPA hazardous waste number U058, must
conform with USEPA regulations in storage, transportation, treatment and
disposal of waste.
A potential candidate for rotary kiln
incineration at a temperature range of 820 to 1,600 deg C and residence times of
seconds for liquids and gases, and hours for solids. A potential candidate for
fluidized bed incineration at a temperature range of 450 to 980 deg C and
residence times of seconds for liquids and gases, and longer for solids.
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All
contaminated disposables should be contained in sealable bags for transfer to
larger waste containers. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All
bottles must be discarded as contaminated waste after decontamination of the
biohazard cabinet. All protective apparel (gown, gloves, goggles, and
respirator) should be discarded as contaminated waste. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
contaminated filters must be removed, bagged in thick plastic and prepared for
disposal in a hazardous waste dump site or incinerator licensed by the
Environmental Protection Agency (EPA). /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The
gown should be removed and placed in a sealable container before removal of the
inner gloves. The inner gloves should be removed last and placed in the
container with the gown. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Hazardous drug waste should be placed in specially marked (specifically labeled
CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers.
These receptacles should be kept in all areas where the drugs are commonly used.
All and only hazardous drug waste should be placed in them. Receptacles used for
glass fragments, needles, and syringes should be puncture resistant. Hazardous
drug waste should not be mixed with any other waste. Waste containers should be
handled with uncontaminated gloves. ... Gloves, gowns, drug vials, etc, should
be sealed in specially labeled (CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic
bags or leakproof containers. ... All hazardous waste collected from drug
preparation and patient-care areas should be held in a secure place in labeled,
leakproof drums or cartons (as required by state or local regulation or disposal
contractor) until disposal. This waste should be disposed of as hazardous or
toxic waste in an EPA-permitted state-licensed hazardous waste incinerator.
Transport to an offsite incinerator should be done by a contractor licensed to
handle and transport hazardous waste. ... If access to an appropriately licensed
incinerator is not available, transport to and burial in an EPA-licensed
hazardous waste dump site is an acceptable alternative. While there are concerns
that destruction of carcinogens by incineration may be incomplete, newer
technologies and stringent licensing criteria have improved this disposal
method. ... Chemical deactivation of hazardous drugs should be undertaken only
by individuals who are thoroughly familiar with the chemicals and the procedures
required to complete such a task. The IARC recently published a monograph
describing methods for chemical destruction of some cytotoxic (antineoplastic)
drugs in the laboratory setting. The chemicals and equipment described, however,
are not generally found in the clinical setting, and many of the deactivating
chemicals are toxic and hazardous. Most procedures require the use of a chemical
fume hood. The procedures are generally difficult, and the deactivation is not
always complete. Serious consideration should be given to the negative aspects
of chemical deactivation before one commits to such a course of action. /Antineoplastic
agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/
Regulatory agencies such as the EPA and state solid and hazardous waste agencies
and local air and water quality control boards must be consulted regarding the
classification and appropriate disposal of drugs that are defined as hazardous
or toxic chemicals. EPA categorizes several of the antineoplastic agents as
toxic wastes, while many states are more stringent and include as carcinogens
certain cytotoxic drugs and hormonal preparations. EPA also allows exemptions
from toxic waste regulations for small quantity generators, whereas certain
states do not. It is critical to research these regulations when disposal
procedures are being established. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If
the biological safety cabinets is equipped with a drainpipe and valve, it may be
used to collect rinse water. The collection vessel used must fit well around the
drain valve and not allow splashing. Gauze may be used around the connection to
prevent aerosol from escaping. The collection vessel must have a tight fitting
cover, and all rinse water (gauze, if used) must be disposed of as contaminated
waste. /Antineoplastic agents/
Occupational Exposure Standards:
Manufacturing/Use Information:
Major Uses:
Therap Cat: Antineoplastic
Immunosupressive
Antineoplastic for treatment of leukemia, etc;
tested for use in chemical shearing of sheep and as an insect chemosterilant.
MEDICATION
MEDICATION (VET)
Methods of Manufacturing:
Cyclophosphamide can be prepared by treating
N,N-bis(B-chloroethyl)-phosphamide dichloride with
propanolamine in the presence of trimethylamine and dioxane.
Prepn: H. Arnold et al., Naturwiss 45, 64
(1957); eidem, Nature 181, 931 (1958); H. Arnold, F. Bourseaux, Angew Chem. 70,
539 (1958).
Formulations/Preparations:
CYCLOPHOSPHAMIDE IS SUPPLIED AS 25 & 50 MG
TABLETS & AS A POWDER (100 TO 2000 MG) IN STERILE VIALS.
Grade: USP, measured as containing 95.0 -
105.0% active ingredient calculated as the monohydrate, 5.7 - 6.8% max. water
content, 0.002% max. heavy metals, and producing an aqueous solution (1 in 100)
at pH 3.9 - 7.1.
Available as 25 and 50 mg tablets ... and in
vials for injection in amounts of 100, 200 or 500 mg measured as containing 90.0
- 110.0% of the stated amount of anhydrous cyclophosphamide.
Consumption Patterns:
Total US sales are 600 kg/year (1975)
U. S. Production:
Not produced in the US.
U. S. Imports:
No data were available on the quantities
imported.
Laboratory Methods:
Clinical Laboratory Methods:
SAMPLE MATRIX: BLOOD AND URINE. ASSAY
PROCEDURE: GAS CHROMATOGRAPHY WITH NITROGEN PHOSPHORUS DETECTION; WHITING B ET
AL, BR J CLIN PHARMACOL 6: 373 (1978). THIN-LAYER CHROMATOGRAPHY WITH
SCINTILLATION SPECTROMETRY; WAGNER T ET AL; CANCER RES 37: 2592 (1977).
Analytic Laboratory Methods:
SAMPLE MATRIX: IN FORMULATIONS. ASSAY
PROCEDURES: HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH ULTRA-VIOLET DETECTION;
KENSLER TT ET AL; J PHARM SCI 68: 172 (1979). GAS CHROMATOGRAPHY WITH FLAME
IONIZATION DETECTION; US PHARMACOPEIAL CONVENTION, INC. THE US PHARMACOPEIA,
15TH ED, ROCKVILLE, MD, PAGES 189-190. /FROM TABLE/
Method 3640A Gel Permeation Chromatography
(GPC) Cleanup Procedure. Gel permeation chromatography with high performance
liquid chromatography. No detection limit reported.
Estimation of nitrogen, phosphorus, or
chloride content; colorimetric analysis, based on the intensity of a cobalt
thiocyanate-cyclophosphamide complex or by use of 4-(4'-nitrobenzyl)pyridine
after hydrolysis; titrimetric analysis, after precipitation of the digested
material by quinoline and citric-molybdic acid solution; and infrared
spectrometry (the method with the most specificity). Also gas-liquid
chromatography and mass spectrometry.
Special References:
Special Reports:
U.S. Department of Health & Human
Services/National Toxicology Program; 9th Report on Carcinogens. National
Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000)
Anderson D et al; Mutat Res 330 (1-2): 115-81
(1995). Cyclophosphamide: Review of its Mutagenicity for an Assessment of
Potential Germ Cell Risks.
Synonyms and Identifiers:
Related HSDB Records:
177 [ACROLEIN] (Metabolite)
Synonyms:
B 518
**PEER REVIEWED**
ASTA B 518
**PEER REVIEWED**
1-BIS(2-CHLOROETHYL)AMINO-1-OXO-2-AZA-5-OXAPHOSPHORIDIN
**PEER REVIEWED**
2-(BIS(2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZOPHOSPHORINE
2-OXIDE
**PEER REVIEWED**
BIS(2-CHLOROETHYL)PHOSPHAMIDE
CYCLIC PROPANOLAMIDE ESTER
**PEER REVIEWED**
BIS(2-CHLOROETHYL)PHOSPHORAMIDE
CYCLIC PROPANOLAMIDE ESTER
**PEER REVIEWED**
N,N-BIS(BETA-CHLOROETHYL)-N',O-PROPYLENEPHOSPHORIC
ACID ESTER DIAMIDE
**PEER REVIEWED**
N,N-BIS(2-CHLOROETHYL)-N',O-PROPYLENEPHOSPHORIC
ACID ESTER DIAMIDE
**PEER REVIEWED**
N,N-BIS(2-CHLOROETHYL)TETRAHYDRO-2H-1,3,2-OXAZAPHOSPHORIN-2-AMINE
2-OXIDE
**PEER REVIEWED**
N,N-BIS(BETA-CHLOROETHYL)N',O-TRIMETHYLENEPHOSPHORIC
ACID ESTER DIAMIDE
**PEER REVIEWED**
CLAFEN
**PEER REVIEWED**
CLAPHENE
**PEER REVIEWED**
CYCLOPHOSPHAMID
**PEER REVIEWED**
CYCLOPHOSPHAN
**PEER REVIEWED**
CYCLOPHOSPHANE
**PEER REVIEWED**
CYTOPHOSPHAN
**PEER REVIEWED**
CYTOPHOSPHANE
**PEER REVIEWED**
CYTOXAN
**PEER REVIEWED**
ENDOXAN
**PEER REVIEWED**
GENOXAL
**PEER REVIEWED**
NSC 26271
**PEER REVIEWED**
2H-1,3,2-OXAZAPHOSPHORIN-2-AMINE, N,N-BIS(2-CHLOROETHYL)TETRAHYDRO-,
2-OXIDE
**PEER REVIEWED**
2H-1,3,2-OXAZAPHOSPHORINE, 2-(BIS(2-CHLOROETHYL)AMINO)TETRAHYDRO-,
2-OXIDE
**PEER REVIEWED**
PROCYTOX
**PEER REVIEWED**
SENDOXAN
**PEER REVIEWED**
Associated Chemicals:
Cyclophosphamide monohydrate;6055-19-2
Formulations/Preparations:
CYCLOPHOSPHAMIDE IS SUPPLIED AS 25 & 50 MG
TABLETS & AS A POWDER (100 TO 2000 MG) IN STERILE VIALS.
Grade: USP, measured as containing 95.0 -
105.0% active ingredient calculated as the monohydrate, 5.7 - 6.8% max. water
content, 0.002% max. heavy metals, and producing an aqueous solution (1 in 100)
at pH 3.9 - 7.1.
Available as 25 and 50 mg tablets ... and in
vials for injection in amounts of 100, 200 or 500 mg measured as containing 90.0
- 110.0% of the stated amount of anhydrous cyclophosphamide.
EPA Hazardous Waste Number:
U058; A toxic waste when a discarded
commercial chemical product or manufacturing chemical intermediate or an
off-specification commercial chemical product or manufacturing chemical
intermediate.
RTECS Number:
NIOSH/RP5950000
Administrative Information:
Hazardous Substances Databank Number: 3047
Last Revision Date: 20020829
Last Review Date: Reviewed by SRP on 5/11/2002
Great Lake Chemical Corporation and the Pathfinders Camp