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PubMed1986

Treatment of trilateral retinoblastoma with vincristine and cyclophosphamide.

Current therapy for patients with trilateral retinoblastoma, consisting primarily of surgical intervention and radiotherapy, has resulted in no long-term survivors. The use of adjuvant chemotherapy has not improved this outcome. After observing a tumor response to cyclophosphamide in a patient with suprasellar retinoblastoma, we treated a subsequent patient with trilateral retinoblastoma with both vincristine and cyclophosphamide. Objective tumor regression resulted. Although the tumor ultimately progressed in both patients, these findings suggest that vincristine and cyclophosphamide are active in patients with intracranial (trilateral) retinoblastoma.

Cyclophosphamide↗
PubMed1993

NADPH-dependent enzyme-catalyzed reduction of aldophosphamide, the pivotal metabolite of cyclophosphamide.

One of the metabolites found in the urine of mammals given the prodrug cyclophosphamide is alcophosphamide, an alcohol. It is most probably generated from cyclophosphamide via aldophosphamide, an aldehyde which otherwise can directly give rise to phosphoramide mustard; the latter effects the cytotoxic action of cyclophosphamide and other oxazaphosphorines. It has already been demonstrated that horse liver alcohol dehydrogenase catalyzes the reduction of aldophosphamide to alcophosphamide. Herein, we report that aldose reductase and aldehyde reductase purified from human placenta also catalyze this reaction. The Km values for aldose reductase- and aldehyde reductase-catalyzed reduction of aldophosphamide to alcophosphamide were 0.15 and 1.6 mM, respectively. Aldose reductase and aldehyde reductase accounted for 94 and 6%, respectively, of total placental pyridine nucleotide-dependent enzyme-catalyzed aldophosphamide (160 microM) reduction. Aldose reductase-catalyzed reduction of aldophosphamide appeared to be noncompetitively inhibited by sorbinil; the Ki value was 0.4 microM. The in vivo significance of these observations is uncertain but could be of some magnitude since alcophosphamide is known to be only weakly cytotoxic.

Alcohol Oxidoreductases↗
PubMed1980

Determination of cyclophosphamide in urine, serum and cerebrospinal fluid of multiple sclerosis patients by field desorption mass spectrometry.

The levels of cyclophosphamide in samples of urine, serum and cerebrospinal fluid of multiple sclerosis patients, who had received the drug orally (4 x 100 mg/day) have been determined by field desorption mass spectrometry using the principle of stable isotope dilution. After thorough preparation of the samples, concentrations of cyclophosphamide of 10 to 60 micrograms/ml in urine and 200 to 400 ng/ml in serum and cerebrospinal fluid have been determined from 0.6-3 ml samples. The first quantitative data for cyclophosphamide in cerebrospinal fluid of multiple sclerosis patients could be established without the use of radioactive material. The relatively high level of the parent drug found in the fluid at the end of a 3-weeks treatment may shed some light on the mechanism of action of this drug in the treatment of the disease.

Cyclophosphamide↗
PubMed1983

Cyclophosphamide pretreatment in tumor cryotherapy: a comparison with alternative drugs.

The method of Turk and Lagrange for modulating immune responses in favor of the cell-mediated effector arm by using single high doses of cyclophosphamide 3 days before antigen has previously been shown to cause decreased rates of local tumor recurrence when adapted as an adjunctive therapy to cryosurgery in a murine model. This series of experiments compares cyclophosphamide, azathioprine, and methotrexate against cryosurgery alone in the same therapeutic protocol. Only cyclophosphamide gave enhanced numbers of cures; azathioprine caused an increase in metastases arising concurrently with local tumor recrudescence.

Animals↗
PubMed1988

Randomised trial comparing combinations of cyclophosphamide and cisplatin without or with doxorubicin or 4'-epi-doxorubicin in the treatment of advanced ovarian cancer.

Forty-eight patients with FIGO stage III and IV epithelial carcinomas of the ovary were entered in this randomised trial. Radical surgery was performed and no residual tumor with a diameter greater than 2 cm was left behind. Of these patients 62.5% (10/16) had a complete or partial response on cyclophosphamide + cisplatin (CP) 87.5% (14/16) on cyclophosphamide + doxorubicin + cisplatin (CAP) and cyclophosphamide + 4'-epi-doxorubicin + cisplatin (CEP). The median time to progression was 3.5 months on CP, 12.5 months on CAP and 11.0 months on CEP. Patients treated with CAP combination chemotherapy had generally longer progression-free survival (log rank chi 2 = 5.4; P = 0.04). No significant difference was found, however, between patients on CAP and CEP. The median survival times were 12.5 months on CP, 26.5 months on CAP and 14.0 months on CEP. Patients treated with CAP combination chemotherapy had generally longer survival (logrank chi 2 = 9.08; P = 0.0099). No significant difference was found, however, between patients on CAP and CEP in terms of survival. Asymptomatic mild-to-moderate laboratory test toxicity occurred in 6-12% of patients on CP, 6-12% on CAP and no toxicity of this type and grade on CEP. Nausea and vomiting were also less severe and less frequent in the CEP group. Cardiotoxicity was seen in 12.5% (2/16) only in the CAP group.

Adult↗
PubMed1987

Cyclophosphamide treatment used to manipulate the immune response for the production of monoclonal antibodies.

After immunization with a complex mixture of antigens, a considerable bias toward obtaining monoclonal antibodies to immunodominant determinants exists. By selectively killing antigen-stimulated lymphocytes, the cytotoxic drug cyclophosphamide can be used to manipulate the bias of the normal immune response. Cyclophosphamide has been used to tolerize mice to one set of antigens followed by immunization with a similar but slightly different set of antigens. This approach yields an enhanced frequency of antibodies that distinguish the two sets of antigens. Cyclophosphamide treatment has also allowed us to produce monoclonal antibodies to weakly immunogenic glycosaminoglycans and to obtain a high frequency of apparently anti-idiotypic antibodies.

Animals↗
PubMed1994

Urinary cyclophosphamide excretion and chromosomal aberrations in peripheral blood lymphocytes after occupational exposure to antineoplastic agents.

In this study we have compared the results of a method for the detection of cyclophosphamide in urine and the results of analysis of chromosomal aberrations in peripheral blood lymphocytes of four groups of subjects with various exposure statuses. These groups are 17 Dutch and 11 Czech exposed workers (mainly hospital nurses and pharmacy technicians) handling antineoplastic agents and 35 Dutch and 23 Czech controls (nurses, medical doctors, pharmacy and lab technicians) not handling these drugs. The groups were subdivided into smokers and non-smokers because of a confounding effect of smoking. Within the Dutch groups, the percentage of aberrant cells and the number of breaks per cell were increased for smokers compared to non-smokers. The percentage of aberrant cells was increased in Dutch exposed workers in comparison with Dutch control workers. Within the Czech groups the percentage of aberrant cells and the number of breaks per cell were increased in exposed workers in comparison with control workers. However, both Dutch and Czech smokers mainly contributed to the increase. The results suggest an additive effect of exposure and smoking in the Dutch subjects and a more than additive effect in the Czech subjects. In urine samples of three out of 11 Dutch exposed workers cyclophosphamide was found in a range of 0.1-0.5 micrograms/24 h. Higher levels were detected in the urine of eight out of 11 Czech exposed workers, a range of 0.1-2.9 micrograms/24 h. No correlation was observed between the amounts of cyclophosphamide excreted in urine on the one hand and the percentage of aberrant cells and the number of breaks per cell on the other hand. The present study is the first study showing that hospital workers having an increase in chromosome aberrations related to their work are exposed to at least one antineoplastic agent.

Adult↗
PubMed1995

Cyclophosphamide-induced synaptonemal complex damage during meiotic prophase of female Rattus norvegicus.

The reproductive system can be especially sensitive to the toxic, carcinogenic or mutagenic effects of alkylating agents. However, since studies of such effects on germ cells are complex, their analysis has been frequently overlooked. In humans, occupational or therapeutic exposure to cyclophosphamide has been associated with male (azoospermia) and female (ovarian failure) sterility or infertility. In this work, we have studied the effect of cyclophosphamide on the formation of the synaptonemal complexes in female rat fetuses. Our results indicate that cyclophosphamide administered at 16 days of gestation, when most germ cells are in a proliferative stage in the female rat, significantly increases the frequency of synaptonemal complex and nucleolar fragmentation in a dose-dependent way.

Animals↗
PubMed1992

Effect of cyclophosphamide immunosuppression on the immunity of turkeys to viral rhinotracheitis.

Turkey poults, free of antibodies to turkey rhinotracheitis (TRT) virus were treated with cyclophosphamide on days 1, 2 and 3 after hatching and vaccinated by eyedrop when 10 days old with a Vero cell-attenuated preparation of TRT virus. No ELISA antibodies to TRT virus developed in the sera of these poults but they were as resistant to virulent virus challenge 21 days later as vaccinated groups which were not cyclophosphamide-treated but produced humoral antibodies. Following challenge with virulent virus at 31 days old cyclophosphamide-treated unvaccinated poults developed a more severe clinical response than untreated birds and had higher virus titres in tracheal swabs. The findings show that the respiratory tract of turkeys may be resistant to TRT despite the absence of ELISA antibodies in the serum.

Animals↗
PubMed1976

Synthesis of steroidal cyclophosphamides.

The Reformatsky product of estrone methyl ether and ethyl bromo-acetate was transformed by two separate routes to 21-amino-3-methoxy-17alpha-pregna-1,3,5(10)-trien-17beta-ol (9). Cyclization with bis- (2-chloroethyl) phosphoramide dichloride produced the steroidal cyclophosphamide 10. Analogous syntheses transformed androstenolone into steroidal cyclophosphamide 20 and androstenedione into steroidal cyclophosphamide 28.

Androstenedione↗
PubMed1983

Cyclophosphamide-induced in vivo sister chromatid exchange in Mus Musculus. II: Effect of age and genotype on sister chromatid exchange, micronuclei and metaphase index.

In vivo cyclophosphamide-induced sister chromatid exchanges (SCEs) micronuclei, and metaphase indices were assessed in two age groups (10.8 +/- 0.9 weeks' an 33.1 +/- 1.3 weeks' old) of female mice from three genetic strains (C3H/S, C57BL/6J, and Balb/c). In general, older animals showed diminished SCE induction over their younger counterparts. The relative difference between individuals of the two ages is strain-dependent. Unlike C57BL/6J and Balb/c, strain C3H/S showed significantly lower SCE values in the older animals at every cyclophosphamide treatment. It may reflect on the possible involvement of genetic determinant(s) for the component(s) of SCE formation during aging. Frequencies of micronuclei, however, were consistently higher in older animals than in their younger counterparts. Furthermore, cytotoxicity of cyclophosphamide, as reflected in metaphase indices, was also higher in older animals. Lower metaphase indices associated with higher micronuclei levels in older individuals may suggest a decline in the rate of cellular replication in these animals. Furthermore, the lower metaphase indices associated with lower SCE values, and increasing micronuclei levels accompanied by decreasing SCE frequencies in older animals, may reflect reduced DNA repair ability during aging. These results support the hypothesis of genotype-dependent decline in the rate of DNA repair and replication during aging, particularly under stressed conditions.

Aging↗
PubMed1979

Late hemorrhagic cystitis following low-dose cyclophosphamide therapy.

Hemorrhagic cystitis is a recognized acute complication of cyclophosphamide (Cytoxan) therapy in the treatment of malignant disease. More recently, lower dose, long-term cyclophosphamide therapy has been used in the treatment of autoimmune diseases including rheumatoid arthritis. In 3 patients hemorrhagic cystitis developed after long-term cyclophosphamide therapy for rheumatoid arthritis. Even in low dosage, this drug may cause hemorrhagic cystitis.

Aged↗
PubMed1980

Bladder cancer following administration of cyclophosphamide.

The relationship between cyclophosphamide and hemorrhagic cystitis is well documented; its role in inducing bladder cancer is less clear. To date, 18 cases of cyclophosphamide-associated bladder tumors have been reported. We present 3 additional cases of transitional cell bladder cancer, all preceded by hemorrhagic cystitis. Data implicating cyclophosphamide as a direct carcinogen as well as an immunosuppressive agent allowing bladder tumor development in the compromised host are discussed. While no direct relationship has been established, we suggest patients receiving this drug are at risk for developing bladder cancer, more likely transitional cell rather than squamous cell as has been reported previously.

Carcinoma, Small Cell↗
PubMed1982

Prevention of cyclophosphamide-induced hemorrhagic cystitis.

The occurrence of hemorrhagic cystitis with the use of high-dose cyclophosphamide is thought to be a toxic effect of cyclophosphamide metabolites directly on the bladder mucosa. To decrease both the concentration of metabolites in contact with the bladder mucosa and the time of such contact, a regimen of diuresis and frequent voiding or catheter drainage was instituted in patients at risk for the development of hemorrhage. Prior to institution of this regimen, 8 of 97 patients experienced massive clot-producing hemorrhage, three-quarters of whom died as a direct result of such hemorrhage. Subsequent to use of this regimen, only 1 of 198 patients experienced this degree of hemorrhage. Although this is only a phase II study, the dramatic decrease in the incidence of hemorrhage strongly suggests the efficacy of this regimen in decreasing the potential morbidity associated with cyclophosphamide-induced hemorrhagic cystitis.

Cyclophosphamide↗
PubMed1991

Cyclophosphamide-associated carcinoma of urothelium: modalities for prevention.

The relationship between the cyclophosphamide metabolite acrolein and hemorrhagic cystitis is well documented. Its role in inducing bladder cancer is not clear. There are at least 35 cases of cyclophosphamide-associated bladder cancer in the literature to date. We report 3 additional cases of transitional cell carcinoma of the bladder. Literature assessing the relative risk of bladder cancer associated with cyclophosphamide therapy is reviewed as are methods for decreasing the toxic effects on the urothelium of the metabolite acrolein.

Acrolein↗
PubMed1984

Cyclophosphamide-induced interstitial pneumonitis in a patient with ovarian carcinoma.

A 40-year-old female with ovarian cancer being treated with daily oral cyclophosphamide developed fatal interstitial pneumonitis. Autopsy did not show any evidence of ovarian cancer. The review of the literature revealed eight reported cases of cyclophosphamide-induced interstitial pneumonitis and fibrosis. The case is reported to alert gynecologists to this rare but lethal complication of cyclophosphamide.

Adult↗
PubMed1990

Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer.

From 1 September 1981 to 1 January 1987, 118 patients with FIGO Stage IB, IC, IIA, IIB, and IIC epithelial ovarian cancer were randomized to abdominal irradiation or pelvic irradiation + cyclophosphamide. There was no difference between the regimens with respect to recurrence-free survival (55%) and 4-year overall survival (63%). At routine second-look laparotomy, 16% of patients without clinical detectable tumor showed recurrence. Twenty-five percent of the patients treated with pelvic irradiation + cyclophosphamide had hemorrhagic cystitis, probably caused by radiation damage and cyclophosphamide cystitis. Eight percent had late gastrointestinal symptoms requiring surgery.

Abdomen↗
PubMed1985

Attenuation of cyclophosphamide-induced taste aversions in mice by prochlorperazine, delta 9-tetrahydrocannabinol, nabilone and levonantradol.

A series of experiments were performed with adult CD-1 male mice to evaluate the antiemetic effects of several compounds using the conditioned taste aversion procedure. The antiemetics were administered IP immediately prior to a 30-min conditioning trial in which a novel tasting solution (0.3% saccharin) was presented to the subjects. The emetics, apomorphine and the cancer chemotherapeutic drug cyclophosphamide, were given IP immediately after the conditioning trial at doses that induced taste aversions. Three days later the mice received a two bottle preference test (saccharin vs. water) and the percent saccharin consumed of the total fluid intake was calculated. Doses of the phenothiazine antiemetic prochlorperazine (1 and 3 mg/kg) attenuated the aversions produced by 0.3 and 1.0 mg/kg apomorphine. Doses of drugs currently approved or under clinical investigation as antiemetics in conjunction with cancer chemotherapy, i.e., prochlorperazine (1.0 mg/kg), delta 9-tetrahydrocannabinol (0.3 and 1.0 mg/kg) and nabilone (0.01 and 0.03 mg/kg), significantly attenuated the taste aversions induced by cyclophosphamide. Levonantradol at doses of 0.03 and 0.06 mg/kg, however, did not attenuate cyclophosphamide-induced taste aversions. Conditioned taste aversions produced by emetic drugs warrants investigation as a model for evaluating potential antiemetics.

Animals↗