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PubMed1975

The quantitation of cyclophosphamide in human blood and urine by mass spectrometry-stable isotope dilution.

The levels of cyclophosphamide in the blood and the urine of patients have been monitored by direct insertion, electron impact mass spectrometry using the principle of stable isotope dilution. When a tetradeuterated analogue of the drug was added to a sample of blood or urine the concentration of cyclophosphamide could be determined from the ratio of the intensities of the signals (M-CH2 C1) characteristic for cyclophosphamide and the tetradeuterated analogue present in the mass spectrum of a chloroform extract. The procedure is highly specific for cyclophosphamide and obviates the need to use radioactively labelled cyclophosphamide for quantitation of the drug in man.

Carcinoma, Small Cell↗

PubMed1976

Clinical effects of cyclophosphamide in Guillain-Barré polyneuritis.

(1) Fifteen patients with severe Guillain-Barré polyneuritis in progression were treated with cyclophosphamide in a total of 23 courses. The illnesses in 11 patients were monophasic, 2 were biphasic and 1 was of the chronic, relapsing variety; another was possibly biphasic. Length of illness prior to first course of cyclophosphamide was as follows: less than 1 week, 3; 1-4 weeks, 9; greater than 4 weeks, 3. (2) Progression stopped in association with 21 courses of treatment, in 6 before the treatment course was finished and in 15 an average of 3 days after the last dose. Improvement began during or following 19 courses. (3) Time when progression stopped, time from end of progression to beginning of improvement, and subsequent rate of recovery, suggest that cyclophosphamide made a significant contribution to the recovery processes in 13 patients. (4) Ultimate degree of recovery was not significantly different from that expected in conventionally treated patients with monophasic illnesses. (5) Reversible alopoecia was the only significant complication attributable to cyclophosphamide toxicity. (6) Our experience suggests that further evaluation of cyclophosphamide should include the use of controls and earlier treatment.

Adolescent↗

PubMed1988

Influence of dietary carrot on cytostatic drug activity of cyclophosphamide and its main directly acting metabolite: induction of sister-chromatid exchanges in normal human lymphocytes, Chinese hamster ovary cells, and their DNA repair-deficient cell lines.

We have utilized an in vivo drug metabolism technique (i.e. injecting the chemical into rat and isolating plasma with metabolites from blood) for detecting the genotoxicity of indirectly acting cyclophosphamide and its directly acting metabolite phosphoramide mustard in cultures of human peripheral blood lymphocytes of normal individuals, Fanconi's anaemia (FA) and aplastic anaemia (AA) patients, wild-type Chinese hamster ovary cells (CHO) and its DNA repair-deficient mutant 43-3B cells. In addition, the influence of dietary carrot on the clastogenic activity of these 2 chemicals in all the different cell types was studied. The genotoxicity was assessed by the ability of the metabolites of these agents to induce sister-chromatid exchanges in the treated cells. A dose-dependent increase in the frequencies of sister-chromatid exchanges was observed in all cell strains following treatment with activated metabolites of cyclophosphamide or phosphoramide mustard. The sensitivity of lymphocytes from normal donors, FA and AA patients to these 2 chemicals was similar. In CHO cell lines the induced frequency of sister-chromatid exchanges was slightly higher after treatment with the metabolites of cyclophosphamide than with phosphoramide mustard. The mutant 43-3B cells responded with higher frequencies of SCEs when compared to the wild-type CHO cells, about 1.5-2-fold, at low doses. Pretreating of rats with fresh carrot juice effectively inhibited the increase in the frequencies of sister-chromatid exchanges induced by cyclophosphamide in wild-type and mutant CHO cells (P less than 0.01), and to a lesser extent in human lymphocytes (p less than 0.05). In contrast, no inhibitory effect was observed in any of these cell types in combination of dietary carrot for direct acting phosphoramide mustard on the frequency of induced sister-chromatid exchanges. The possibility that dietary carrot exerts its antimutagenic effect by affecting the processes of enzymatic activation of cyclophosphamide is discussed.

Anemia, Aplastic↗

PubMed1988

Role of the 4-hydroxy intermediate in the in vitro embryotoxicity of cyclophosphamide and dechlorocyclophosphamide.

Cyclophosphamide must be metabolically activated to produce malformations in cultured rat embryos. A 4-hydroxylated intermediate, 4-hydroxycyclophosphamide is initially formed during this activation. While 4-hydroxycyclophosphamide (and/or its open-ring tautomer, aldophosphamide) is believed to act as a transport form in mediating the antineoplastic activity of cyclophosphamide, its role in the teratogenicity of this drug is not known. In this study the effects of two "preactivated" cyclophosphamide analogs on cultured Day 10 rat embryos were determined. The first analog, 4-hydroperoxycyclophosphamide, is converted to 4-hydroxycyclophosphamide in aqueous solutions, releasing both acrolein and phosphoramide mustard, while the second, 4-hydroperoxydechlorocyclophosphamide, releases, in a similar manner, acrolein and the inactive metabolite, phosphoric acid diamide. Both cyclophosphamide analogs were teratogenic, embryolethal, and growth retarding in vitro, but the effective concentrations and the types of malformations produced were different. 4-Hydroperoxycyclophosphamide produced embryo deaths and malformations and decreases in embryonic growth and protein content at concentrations in the range of 5 to 25 microM. In contrast, 4-hydroperoxydechlorocyclophosphamide did not produce embryo deaths at concentrations below 100 microM and produced embryo malformations and growth retardation only at 125 microM. The concentration-response curve and the spectrum of malformations produced by 4-hydroperoxycyclophosphamide resembled those previously reported for phosphoramide mustard, while the concentration-response curve and types of malformations produced by 4-hydroperoxydechlorocyclophosphamide more closely resembled those observed with acrolein. Thus, the 4-hydroxy intermediates are similar as teratogens to the most potent of the metabolites which they produce; the 4-hydroxy compounds may serve as a transport form of cyclophosphamide but do not appear themselves to have a major role in teratogenicity.

Animals↗

PubMed1983

High incidence of neoplasms in female NZB/NZW mice treated with pulse doses of cyclophosphamide.

The immunosuppressive properties of cyclophosphamide prevent formation of anti-DNA antibodies and prolong lifespans in autoimmune NZB/NZW mice, an animal model of systemic lupus erythematosus. In the current study, NZB/NZW mice were treated with weekly doses of cyclophosphamide to determine if intermittent pulses of the drug were effective therapy. Life-long treatment with cyclophosphamide, 56 mg/kg/week, was started at the mean age of 6 weeks; results were compared with saline-injected control mice. Pulse therapy with cyclophosphamide suppressed anti-DNA antibody levels, prevented severe glomerulonephritis and prolonged longevity. Seventeen of 19 treated mice developed neoplasms; 7 of these immunosuppressed animals had 2 to 4 separate neoplasms. Examination of earlier studies in this laboratory in which NZB/NZW mice were treated each day with cyclophosphamide showed that daily and weekly therapeutic regimens had similar immunosuppressive and oncogenic effects.

Animals↗

PubMed1983

Effect of procarbazine and cyclophosphamide on chromosome breakage in Fanconi anemia cells: relevance to bone marrow transplantation.

Fanconi anemia (FA) patients develop stem cell defect-based pancytopenia for which bone marrow transplantation offers the potential for correction. Recently, it has become apparent that the outcome of marrow transplantation in FA patients is poor because of the hypersensitivity of these patients to the pretransplantation conditioning regimen which includes immunosuppression with high doses of the difunctional alkylating agent cyclophosphamide. In an effort to devise a less toxic immunosuppressive regimen, we compared the clastogenic effect of cyclophosphamide with that of procarbazine in cells from FA patients and normal controls. Activation of the drugs was achieved by two alternative methods, either by injection into rats (the in vivo activation method) or by incubation with a rat-liver microsome system (the in vitro activation method). Increased sister chromatid exchange following treatment of cells with cyclophosphamide or procarbazine was used as an indicator for the presence of activated drug metabolites in the system. Although FA cells were hypersensitive to the clastogenic effect of cyclophosphamide, they were not more sensitive than normal cell to procarbazine-induced chromosome breakage. Procarbazine may thus be a safer drug than cyclophosphamide for conditioning FA patients for bone marrow transplantation.

Anemia, Aplastic↗

PubMed1988

Chemotherapy with maximally tolerable doses of VP 16-213 and cyclophosphamide followed by autologous bone marrow transplantation for the treatment of relapsed or refractory germ cell tumors.

Eleven patients with advanced nonseminomatous germ cell tumors (NSGCT), who relapsed after or were refractory to standard dose cisplatin-based remission induction chemotherapy, were treated in a phase II clinical trial with VP 16-213 2500 mg/m2 and cyclophosphamide 7 g/m2. Both drugs were given in maximally tolerable doses regarding extramedullary toxicity. Urothelial damage due to cyclophosphamide was prevented by the administration of mesnum. Autologous bone marrow was infused on day 7 to prevent long lasting medullary toxicity. Because of the disappointing results in the first three patients, a second treatment step was added. The next eight patients were treated with 2500 mg/m2 VP 16-213 divided and given on days 1-2-3 and after full bone marrow recovery with total doses of VP 16-213 2000 mg/m2 plus cyclophosphamide 7 g/m2 divided and given on days 29-30-31, followed by autologous bone marrow transplantation (ABMT) on day 35. Toxicity to high-dose VP 16-213 plus cyclophosphamide followed by ABMT consisted of mucositis, nausea, vomiting and diarrhea. No cardiac toxicity or hemorrhagic cystitis occurred. The mean duration of leukopenia and thrombopenia was 14 and 13 days respectively. The additional, preceding treatment with VP 16-213 as a single agent caused mucositis, and leukopenia and thrombopenia for a mean number of 9 and 6 days respectively. Seven responses were obtained: two complete responses of 46 and 66+ weeks respectively and five partial responses with a median response duration of 12 weeks. The median survival time was 40 weeks. This regimen of one or two courses with maximally tolerable doses of VP 16-213 plus cyclophosphamide and ABMT is not sufficient to salvage a substantial number of patients with relapsing or refractory NSGCT.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Development and characterisation of a cyclophosphamide resistant variant of the BNML rat model for acute myelocytic leukaemia.

A cyclophosphamide resistant subline (BNML/CPR) was developed in vivo in the BN rat acute myelocytic leukaemia (BNML) model. Full resistance was achieved after in vivo exposure of leukaemic animals to cyclophosphamide with, in total, 15 intraperitoneal injections of 100 mg/kg. The CPR line was cross-resistant to ifosfamide, but less so to mafosfamide. Continuous transplantation of the BNML/CPR line without a cyclophosphamide selection pressure resulted in the emergence of a subline (BNML/CPR greater than S) whose sensitivity to cyclophosphamide was similar to that of the parent BNML/S line. Both in the BNML parent line and in the BNML/CPR greater than S line, a 2p+ marker chromosome was present, whereas a 2p+q+ marker chromosome was characteristic for the BNML/CPR line. The mechanism of cyclophosphamide resistance can now be investigated in the BNML model at the DNA, at the mRNA and at the protein level.

Animals↗

PubMed1995

In vitro murine embryotoxicity of cyclophosphamide in embryos co-cultured with maternal hepatocytes: development and application of a murine embryo-hepatocyte co-culture model.

The technique of whole embryo culture provides a sensitive model to evaluate both the effects, and their underlying mechanisms, of drugs and environmental chemicals on embryonic development, independent of maternal influences. However, before teratogenic expression, many teratogens must be enzymatically bioactivated to toxic reactive intermediates. To detect such proteratogens, the embryo culture model may need to be coupled with an exogenous bioactivating system if maternal and/or placental metabolism is involved. We developed a similar embryo-hepatocyte co-culture system using embryos and maternal hepatocytes from mice, which often are more sensitive than rats to chemical teratogens, and which may have a balance of phase II drug metabolising enzymes more similar to humans. This murine system was then used to evaluate the relative maternal and embryonic contributions to cyclophosphamide embryopathy. Day 9.5 (morning of plug = day 1) murine embryos were co-cultured for 24 h in vitro with primary cultures of murine maternal hepatocytes (> 85% viability). Murine embryos were exposed to cyclophosphamide concentrations (0, 7.5, 15, 25 micrograms/ml), similar to those used in rat embryo culture studies. Murine embryos co-cultured with murine maternal hepatocytes developed normally, as did embryos exposed to cyclophosphamide in the absence of hepatocytes. Maternal hepatocytes were necessary for the expression of cyclophosphamide embryotoxicity, which was concentration-dependent, as demonstrated by increasing severity of reductions in crown rump length, yolk sac diameter and somite number. These results show that the co-culture of murine maternal hepatocytes and embryos is feasible, and suggest that maternal bioactivation is required for murine cyclophosphamide embryopathy.

Animals↗

PubMedDate not supplied

The value of combining the radiosensitizer misonidazole with cyclophosphamide in treating the murine Lewis lung tumor.

Cyclophosphamide and the radiosensitizer misonidazole were combined to determine if any therapeutic benefit could be demonstrated with this combination in treating the murine Lewis lung tumor. The results of our in vivo studies indicated that when various dosage schedules of misonidazole were combined with cyclophosphamide, the tumor effect was greater than when cyclophosphamide was administered alone. However, the increased effect of the two drug combination was determined to be no greater than an additive effect of cyclophosphamide tumor cell toxicity plus misonidazole cytotoxicity. Furthermore, host toxicity was enhanced when the two drugs were combined as indicated by the LD50 assay. We conclude that combining cyclophosphamide with misonidazole offers little if any therapeutic advantage since the increase in host toxicity appears to be as greater as the increase in tumor cell killing.

Animals↗

PubMedDate not supplied

Misonidazole enhances cyclophosphamide toxicity to bone marrow.

Normal bone marrow function was surveyed in animals that received cyclophosphamide after treatment with small, multiple doses of misonidazole. Peripheral blood white cell counts, cell differentials, hematocrits, bone marrow white cell counts and committed granulocyte-macrophage precursors (CFUc) were monitored for several days following treatment with misonidazole and cyclophosphamide. When results obtained from animals treated with physiological saline or misonidazole in advance of cyclophosphamide were compared, no significant differences were noted in routine assays of white blood cell count, cell morphology or hematocrit. Pre-treatment with misonidazole, however, caused a significant reduction in survival and delay in recovery of bone marrow CFUc (p less than .01). The combined use of misonidazole and cyclophosphamide also reduced animal survival (DMF = 1.2), with the majority of deaths being attributable to failure of normal hematopoietic function. These results suggest that misonidazole enhances the myelotoxicity associated with cyclophosphamide use. This additional damage is not detectable using routine hematological assays, but is demonstrable in assays of bone marrow stem cells and animal survival studies.

Animals↗

PubMed1994

Etoposide in combination with cyclophosphamide and total body irradiation or busulfan as conditioning for marrow transplantation in adults and children.

PURPOSE: In an attempt to intensify conditioning therapy for bone marrow transplantation of hematologic malignancies, a retrospective three center evaluation of escalating doses of etoposide added to cyclophosphamide and either total body irradiation or busulfan was undertaken. METHODS AND MATERIALS: Seventy-six patients who received etoposide (25-65 mg/kg) added to cyclophosphamide (60-120 mg/kg) and either total body irradiation (12.0-13.2 Gy) or busulfan (12-16 mg/kg) were evaluable for toxicity. Fifty-one of the evaluable patients received allogeneic transplants, while twenty-six received autologous transplants. A comparative analysis of toxicities according to conditioning regimen, donor source and etoposide dose was made. RESULTS: Similar toxicities were observed among the treatment groups with the exception of more frequent skin (p = 0.003) and life threatening hepatic toxicities (p = 0.01) in the busulfan treated patients. Life threatening or fatal toxicities were not influenced by donor source, either when analyzed by treatment group or etoposide dose. Etoposide at a dose of 60-65 mg/kg in combination with TBI and cyclophosphamide was associated with a significantly increased incidence of life threatening or fatal toxicities compared with a combination using a dose of 25-50 mg/kg (15 of 24 vs. 5 of 20; p = 0.013). The maximally tolerated dose of etoposide in combination with busulfan and cyclophosphamide cannot be definitively established in this analysis in part due to the heterogeneity of the patient population and treatment schemes. CONCLUSION: Although toxicities with bone marrow transplant preparative regimens containing etoposide in combination with cyclophosphamide and total body irradiation or busulfan were frequently severe, treatment related mortality risk was believed to be acceptably low.

Adolescent↗

PubMed1987

Determination of cyclophosphamide in whole blood and plasma by reversed-phase high-performance liquid chromatography.

A rapid, simple, and sensitive reversed-phase high-performance liquid chromatographic determination of the cytostatic drug cyclophosphamide in whole blood and plasma has been developed. The pre-chromatography isolation of the drug involves salting-out of acetonitrile with simultaneous extraction of cyclophosphamide from whole blood and plasma. A short column packed with 5-micron reversed-phase octadecylsilane (ODS) spherical particles was used with an isocratic elution of 5 mM potassium phosphate (pH 6.80)-acetonitrile (80:20, v/v). The cyclophosphamide was monitored at 190 nm and 0.40-0.002 a.u.f.s. At a flow-rate of 1.0 ml/min, the retention time of cyclophosphamide was ca. 9 min. The completion time for the assay was less than 20 min and the assay had a detection limit of 0.30 microgram/ml. This method was used to determine the stability of cyclophosphamide in plasma at room temperature and at -10 degrees C.

Chromatography, High Pressure Liquid↗

PubMed1996

High-performance liquid chromatographic determination of the enantiomers of cyclophosphamide in serum.

A high-performance liquid chromatographic (HPLC) achiral-chiral coupled assay to measure the serum concentration of the enantiomers of cyclophosphamide is described. The R- and S-enantiomers of cyclophosphamide were quantified using a 5-cm-long C1 Spherisorb 5-microns column, with switching of the eluent containing racemic cyclophosphamide onto a 10-cm-long alpha 1 acid glycoprotein column. The limit of determination was 1.25 mg l-1 for each enantiomer and the ratio of the enantiomers over the range 2.5 to 100 mg l-1 was I. Serum enantiomer concentrations in blood samples taken from patients receiving 0.30 to 0.75 gm-2 of intravenous racemic cyclophosphamide could be measured at least three half-lives post dose. In six patients no significant difference in the clearance of R- and S-cyclophosphamide was found.

Antineoplastic Agents↗

PubMed1992

Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 2. Effects on uterine structure and function.

Cyclophosphamide-induced uterine weight loss was evaluated to determine whether it was a function of primary toxicity to the uterus or a secondary response to ovarian toxicity, that is, antral follicle destruction. C57BL/6N mice treated with cyclophosphamide exhibited a reduction in uterine weight concurrent with a decrease in plasma estradiol (E2) concentrations, thereby indicating toxicity to the ovary. However, when E2 concentrations recovered, uterine weight still remained depressed, suggesting that cyclophosphamide also impaired uterine function. Further investigation revealed that cyclophosphamide altered the normal uterotropic response to E2, significantly diminishing the uterine weight gain associated with E2 treatment. We conclude that effects of cyclophosphamide on the uterus involve two components: 1) decreased uterine weight in response to decreased plasma E2 resulting from ovarian toxicity, and 2) an altered response to E2 due to direct uterine toxicity.

Animals↗

PubMed1994

In vivo administration of taurine and niacin modulate cyclophosphamide-induced lung injury.

The antiinflammatory, antioxidant activity of taurine and niacin against cyclophosphamide-induced early lung injury in rats was investigated. A single intraperitoneal injection of cyclophosphamide markedly altered the levels of several biomarkers in bronchoalveolar lavage fluid: total protein, albumin, angiotensin converting enzyme, lactate dehydrogenase, lactate, N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase and lipid peroxidation product were significantly elevated. In contrast, decreased levels of total reduced glutathione (GSH) and ascorbic acid were observed. Cyclophosphamide significantly increased malondialdehyde levels in serum and lung. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione and total sulfhydryl groups. Pretreatment of rats with daily intraperitoneal injection of taurine plus niacin 7 days prior to and 2 days after cyclophosphamide insult significantly inhibited the development of lung injury, prevented the alterations in lavage fluid biomarkers associated with inflammatory reactions, with less lipid peroxidation and restoration of antioxidants. In conclusion, our results suggest that taurine and niacin in combination is efficient in blunting cyclophosphamide-induced pulmonary damage.

Acid Phosphatase↗

PubMed1995

Cyclophosphamide immunosuppression does not permit successful myoblast allotransplantation in mouse.

Cyclophosphamide immunosuppression does not permit successful myoblast allotransplantation in mouse. Myoblast transplantation is a potential treatment for Duchenne muscular dystrophy. In one clinical trial, Duchenne patients were immunosuppressed with cyclophosphamide. We report here that myoblasts from transgenic mice expressing the beta-galactosidase reporter gene transplanted in mdx mice failed to form new muscle fibres when cyclophosphamide (2 or 10 mg kg-1 per day) was used for immunosuppression. At the lowest dose of cyclophosphamide (2 mg kg-1 per day), some mdx recipient mice formed antibodies against donor myoblasts; however, no humoral immune reaction was observed at the highest dose (10 mg kg-1 per day). The failure of transplantation under cyclophosphamide treatment was attributed to the low immunosuppressive activity at a low dose and to the toxic action of a high dose of this drug. These results could explain the lack of success of myoblast transplantation in a previous clinical trial.

Animals↗

PubMed2006

Cytoreduction of lymphoid malignancies and mobilization of blood hematopoietic progenitor cells with high doses of cyclophosphamide and etoposide plus filgrastim.

We evaluated the efficiency of high doses of cyclophosphamide (6 g/m2) and etoposide (2 g/m2) plus filgrastim (granulocyte colony-stimulating factor; G-CSF) to mobilize autologous hematopoietic progenitor cells in patients with non-Hodgkin lymphoma, multiple myeloma, and Waldenström macroglobulinemia. We also evaluated the safety of this regimen and the engraftment kinetics after myeloablative chemotherapy. Seventy-nine patients with high-risk or relapsed/primary refractory non-Hodgkin lymphoma, multiple myeloma, or Waldenström macroglobulinemia were treated. The mobilizing regimen was as follows: cyclophosphamide 600 mg/m2 twice daily for 10 doses, etoposide 200 mg/m2 twice daily for 10 doses (continuous; n=57) or 2 g/m2 over 10 hours on day 5 of etoposide (bolus; n=22), and G-CSF 5 microg/kg/d beginning day 14. Fifty-nine percent of patients achieved the primary end point (a CD34 cell dose of 5 million per kilogram with a single leukapheresis). More bolus etoposide patients achieved the primary end point (86%) compared with continuous etoposide patients (47%; P<.0001). The CD34 cell dose collected was greater in bolus etoposide patients (44 million per kilogram) than in continuous etoposide patients (10.9 million per kilogram; P<.0001). Patients took 3 weeks to recover >500/microL neutrophils and >20000/microL platelets after cyclophosphamide and etoposide. The overall response rate was 69% for non-Hodgkin lymphoma patients and 71% for multiple myeloma/Waldenström macroglobulinemia patients. The treatment-related mortality was 2.5%. Sixteen percent of surviving patients experienced grade>or=3 nonhematologic toxicity. Patients receiving bolus etoposide had significantly less grade>or=2 oral mucositis, less use of total parenteral nutrition, and less need for red blood cell and platelet transfusions. Sixty-four patients (81%) underwent autologous hematopoietic progenitor cell transplantation, with prompt engraftment. Four patients (5%) did not undergo autologous hematopoietic progenitor cell transplantation because of toxicity from high-dose cyclophosphamide and etoposide. We conclude that high doses of cyclophosphamide and etoposide combined with G-CSF are an efficient and safe mobilizing regimen for the collection of hematopoietic progenitor cells during aggressive cytoreduction of tumor burden in patients with lymphoid malignancies.

Adult↗