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PubMed2004

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis.

OBJECTIVE: Pulse cyclophosphamide is the treatment of choice for severe lupus nephritis. However, not all patients respond to this therapy, and gonadal toxicity is of particular concern. Cyclophosphamide is a prodrug that requires activation by cytochrome P450 (CYP) enzymes. We conducted a retrospective cohort study to test whether genetic polymorphisms of these enzymes are associated with the toxicity of, and clinical response to, cyclophosphamide in patients with lupus nephritis. METHODS: Sixty-two patients with proliferative lupus nephritis treated with cyclophosphamide were genotyped for common variant alleles of CYP2B6, 2C19, 2C9, and 3A5. We examined the association between these genotypes and the following clinical end points: development of premature ovarian failure, end-stage renal disease (ESRD), doubling of serum creatinine level, and achievement of complete renal response. RESULTS: The observed frequencies of the variant alleles CYP2B6*5, CYP2C19*2, CYP2C9*2, and CYP3A5*3 were 12.1%, 25.0%, 4.0%, and 75.8%, respectively. Patients who were either heterozygous or homozygous for CYP2C19*2 had a significantly lower risk of developing premature ovarian failure (relative risk 0.10; 95% confidence interval 0.02-0.52), after adjustment for age and total number of cyclophosphamide pulses received. In a survival analysis, patients homozygous for CYP2B6*5 (n = 3) or CYP2C19*2 (n = 4) had a higher probability of reaching ESRD (P = 0.0005) and of doubling the creatinine level (P = 0.0005) as well as a trend toward a lower probability of achieving a complete renal response (P = 0.051). CONCLUSION: Determination of selected cytochrome P450 enzyme genotypes may be valuable for predicting the risk of premature ovarian failure in lupus nephritis patients treated with cyclophosphamide. The association of these genotypes with renal response needs further validation.

Adult↗

PubMed1996

Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation.

Hepatic venoocclusive disease (HVOD) is caused by the disruption of the microcirculation by an as-yet unknown mechanism. Previous in vitro studies with azathioprine, monocrotaline, and dacarbazine suggested that toxins that cause HVOD initially causing HVOD target sinusoidal endothelial cells (SEC) perhaps via profound glutathione (GSH) depletion. The current study examines cyclophosphamide toxicity in SEC and hepatocytes, as well as the interplay between the two cell types. Cyclophosphamide was not directly toxic to SEC, but in coculture of SEC and hepatocytes, cyclophosphamide was significantly more toxic to SEC. Two cyclophosphamide metabolites, 4-hydroperoxycyclophosphamide and acrolein, were equally toxic to SEC, and toxicity occurred at 20-fold-lower concentrations than in hepatocytes. 4-Hydroperoxycyclophosphamide depleted GSH by greater than 95% before inducing cell death in SEC. When hepatocyte-GSH levels were sustained with supplemental methionine and serine in coculture, toxicity in both cell types was diminished. In coculture, SEC are significantly more susceptible than hepatocytes to cyclophosphamide toxicity, and this is likely caused by acrolein generated by the hepatocyte. As seen with other toxins implicated in HVOD, the profound depletion of SEC GSH precedes the onset of toxicity. The degree of cyclophosphamide toxicity induced in SEC is determined by both metabolic activation and GSH detoxification in the hepatocytes.

Acrolein↗

PubMedDate not supplied

Antimitotic drugs (cyclophosphamide and vinblastine) in the male rat. Deaths and behavioral abnormalities in the offspring.

The spermatogenesis and the offspring of male rats treated either with cyclophosphamide alone, or with both cyclophosphamide and vinblastine were investigated. The offspring were evaluated for the mean number of pups per litter, sex ratio, the frequency of apparent external malformations and, within the first 4 months of life, growth and mortality. When they reached adulthood and were between 12 and 16 weeks of age, the offspring were also examined for spontaneous activity and learning capacity. Treatment with cyclophosphamide or cyclophosphamide and vinblastine resulted in a decrease in the number of both primary spermatocytes and spermatids; the effect, however, lasted longer for the combined drug regimen. At birth, the animals sired by the treated males did not show any apparent malformations. However, compared with the control population the mortality rate of the offspring was significantly higher within the first 40 days of life; at adult age, the proportion of animals that failed in the learning ability test was significantly increased and those that did succeed showed impaired learning capacity. The difference, however, was significant only in the male offspring. Finally, the offspring's spontaneous activity was significantly decreased. No difference was found in mortality or behavior between the animals born of the cyclophosphamide or cyclophosphamide plus vinblastine-treated males. The behavioral disorders shown in the adult offspring confirm the existence of a long-term risk of paternal origin. This risk, essentially functional and independent of any morphologic pathology, should be taken into account in the context of environmental genotoxicity.

Animals↗

PubMed1988

Efficacy of mesna in preventing further cyclophosphamide-induced hemorrhagic cystitis.

Mesna is a sulfhydryl compound that reacts with the metabolites of cyclophosphamide that are excreted in the urine and may produce bladder wall irritation. Mesna is converted in the blood to a biochemically inactive compound that is reduced back to mesna in the kidneys. In this way it has the potential to protect the bladder mucosa without interfering with the antineoplastic effect of cyclophosphamide. Twenty-two patients who had developed hemorrhagic cystitis from cyclophosphamide were treated again with cyclophosphamide and mesna prophylaxis. A total of 68 cycles of cyclophosphamide were given with mesna, with a median of three cycles per patient. A recurrence of cystitis was prevented in all but one patient. Thus, mesna is effective in preventing recurrent cystitis in patients receiving further cyclophosphamide.

Adolescent↗

PubMed1994

Combination trial of subcutaneous recombinant alpha 2 b interferon and oral cyclophosphamide in follicular low-grade non-Hodgkin's lymphoma.

The follicular non-Hodgkin's lymphomas (NHL) have been among those tumors demonstrated to show frequent responses to alpha interferon in phase I and II clinical trials. In addition, there are data suggesting that alpha interferon demonstrates synergistic antitumor activity with alkylating agents in animal models for a number of tumors. Based on these data, Cancer and Leukemia Group B (CALGB) undertook a phase II pilot study of the combination of interferon rIFN alpha 2b (2 x 10(6) IU/m2 s.c. tiw) and cyclophosphamide (100 mg/m2 per day orally) with the ultimate purpose of examining this combination as long-term therapy of follicular lymphoma in comparison to oral cyclophosphamide alone. One hundred five advanced stage III or IV eligible patients with pathologically diagnosed International Working Formulation B or C histology were entered on CALGB 8553 to determine toxicity and response rates to the combination. Both previously chemotherapy-treated patients (32) and patients without prior chemotherapy (73) were entered on study. For patients without prior chemotherapy the overall response rate to the combination regimen was 86% with 58% of chemotherapy-treated patients achieving complete response. Chemotherapy-treated patients had a total response rate of 62% with only 25% complete responders. Complete responses in patients without prior chemotherapy were positively correlated with absence of B symptoms, and good performance status and negatively correlated with the histological subtype of follicular mixed small-cleaved and large cell histology (IWF C); only performance status was significantly correlated with response in patients who had previously had chemotherapy. Survival at 5 years is estimated to be 63% for those without chemotherapy and 39% for those previously treated with chemotherapy patients. The maximum toxicities experienced during therapy with the combination regimen of cyclophosphamide and interferon alpha were primarily related to myelosuppression. Sixty-seven percent of patients without prior chemotherapy and 65% of patients receiving prior chemotherapy experienced severe leukopenia while severe thrombocytopenia and anemia occurred in 6-31% of these patients. Non-myelosuppressive toxicities were less frequently seen. These response rates are similar to those achieved in a previous CALGB trial with oral cyclophosphamide as a single agent, although severe myelotoxicity was increased to approximately 60% of patients from less than 10% with the single-agent therapy. The combination of alpha interferon and cyclophosphamide administered in this fashion is safe when peripheral counts are carefully monitored. Randomized studies of this regimen in comparison to oral cyclophosphamide are currently in progress.

Administration, Oral↗

PubMed1984

Metabolic activation of cyclophosphamide by yolk sac endodermal cells of the early chick embryo.

Endodermal cells isolated from the yolk sacs of day 3 chick embryos were able to activate metabolically cyclophosphamide. This was demonstrated by the cytotoxicity of cyclophosphamide to the endodermal cells themselves as well as by the ability of endodermal tissue to mediate a cytotoxic response in coculture with KB cells, a human tumor cell line unable to activate cyclophosphamide. Yolk sac endodermal cells from day 3 embryos were sensitive to cyclophosphamide when the drug was added immediately after the start of culture, but not when the drug was added after 24 hr of culture. The ability to metabolize cyclophosphamide by the day 3 embryo appeared limited to the endodermal cells of the yolk sac as cells derived from neither the embryo proper nor yolk sac mesoderm-ectoderm tissue were positive in these tests. Using whole blastoderms, cyclophosphamide activation was detected as early as 12 hr of egg incubation.

Animals↗

PubMed1992

Paternal cyclophosphamide treatment causes postimplantation loss via inner cell mass-specific cell death.

Treatment of the father with the anticancer alkylating agent cyclophosphamide has negative effects on embryonic development in the rat. Four-week treatment of male rats with a low dose of cyclophosphamide causes a dramatic, dose-dependent increase in postimplantation death of the progeny. Several recent studies have indicated that the paternal genome is required for the development of the extraembryonic tissues. Thus, the purpose of this study was to determine which tissues of the implanting embryo were affected by paternal exposure to cyclophosphamide. Male Sprague-Dawley rats were given cyclophosphamide (6 mg/kg/day) or saline by gavage and bred to untreated female rats after 4 weeks of treatment. Pregnant female rats were killed on day 7 of gestation, and implantation sites were dissected from the uterus, fixed, embedded in Epon for semithin serial sectioning, and stained for subsequent light microscopy. Strikingly, many of the implantation sites of affected embryos sired by treated males displayed an apparently normal trophectoderm enclosing a region of dying cells, containing dark-stained pyknotic nuclei. Very few or no inner cell mass-derived embryonic cells were present in these implantation sites. Therefore, there is a selective death of inner cell mass-derived cells in day 7 implantation sites obtained from the progeny of cyclophosphamide-treated males. The results of this study suggest that treatment of the male with cyclophosphamide can affect paternal genes specifically required for development of the inner cell mass cells of the embryo, without an apparent effect on those genes required for normal trophectoderm.

Animals↗

PubMed2001

Bladder carcinoma associated with cyclophosphamide therapy for ovarian cancer occurring with a latency of 20 years.

BACKGROUND: Cyclophosphamide-induced urothelium cancer of the bladder is a well-known entity. The risk for inducing such cancer grows with duration and dosage of cyclophosphamide therapy. The lag time between termination of treatment and development of urothelial cancer has been observed to be between 9 months and 11 years. Single cases have been reported 14, 16, 17, and 21 years after cyclophosphamide treatment. CASE: We report a case of a bladder cancer occurring after a lag time of 20 years after oral therapy with cyclophosphamide for ovarian cancer. The bladder cancer was detected due to gross hematuria. CONCLUSION: It is of great importance for gynecologists to continue to care for patients who have received long-term cyclophosphamide treatment, even if the treatment was completed decades ago. One possible early symptom of cyclophosphamide-induced bladder cancer is painless hematuria. This can easily be used to detect bladder cancer in women at risk, even after a very long latency period.

Adult↗

PubMed1988

Successful chemoimmunotherapy of murine L1210 lymphatic leukemia with cyclophosphamide and mafosfamide-treated leukemia cells.

Balb/c x DBA/2 F1 mice (CD2F1 mice) bearing L1210 lymphatic (10 L1210 cells i.p. injected on day 0) were subjected to chemoimmunotherapy. They received 100 mg/kg of cyclophosphamide i.p. on day +8 and 10(6) or 10(7) immunogenic L1210 cells treated in vitro with mafosfamide - ASTA Z7654 (L1210-Maf cells) i.p. or i.p. + s.c. on days 0, +3, +6, +9, +12 after the leukemia implantation. About 30% of leukemia-bearing mice receiving cyclophosphamide and L1210-Maf cells after L1210 inoculation were able to reject the leukemia (as compared with 0% after injection of L1210-Maf cells only or 5% after cyclophosphamide administration). Better results (54% of cured mice) were obtained if 10(7) L1210-Maf cells were injected i.p. +s.c. beside cyclophosphamide. Biological response modifiers (BRM's): levamisole, BCG, bestatin did not improve these results in the doses used in the experiment. Augmentation of anti-L1210 therapeutic response is dependent on the administration of cyclophosphamide and L1210-Maf cels. Cyclophosphamide not only reduces the tumor burden but probably can potentiate the L1210-Maf dependent antitumor immunity as well.

Animals↗

PubMed1989

Augmented induction of antitumor cells in vivo by cyclophosphamide fails to benefit antitumor resistance of the host.

The present study was designed to examine whether cyclophosphamide augmented induction of antitumor cells and antitumor resistance in C57BL/6 mice pretreated with mitomycin-C-treated EL4 cells (EL4MMC) plus OK-432, a streptococcal preparation. C57BL/6 mice were pretreated with EL4MMC (10(7] plus OK-432 (2.5 KE) i.p. twice at 1-week intervals. When the mice received an i.p. injection of cyclophosphamide at 200 mg/kg 2 days before the last treatment, the antitumor activity of their spleen cells and peritoneal exudate cells (PEC) was effectively augmented 7-8 days after the last treatment. Splenic antitumor activity disappeared 15 days after the last treatment whereas augmented antitumor activity of the PEC was detected even 28 days after the last treatment. This cyclophosphamide effect was dose-dependent and 200 mg/kg was the most effective among the doses tested. If the EL4MMC plus OK-432 treatment was injected at a s.c. site, it was also effective in combination with cyclophosphamide. The antitumor activity of the PEC from s.c.-pretreated mice, however, was lower than that from i.p.-pretreated mice. Despite the fact that cyclophosphamide effectively augmented induction of antitumor cells in C57BL/6 mice pretreated with EL4MMC plus OK-432, it diminished rather than augmented, under all conditions tested, the ability of the mice to resist a challenge of live EL4 cells. Reduction of antitumor resistance by cyclophosphamide was also observed in an experimental system of a semi-syngeneic host (BDF1) tumor (EL4). These results indicate that augmentation of in vivo induction of certain kinds of antitumor cells does not necessarily result in a beneficial augmentation of the host's ability to resist tumor growth.

Animals↗

PubMed1984

Observations on the effects of cyclophosphamide, phosphoramide mustard and some activated oxazaphosphorines on murine L1210 leukemia.

The L1210 tumor system was used in vitro and in vivo in comparative studies with activated cyclophosphamide analogs, cyclophosphamide and phosphoramide mustard. All the above compounds gave substantial cell kills (5 logs) of L1210 in vivo at doses that were non-toxic, but slight differences were noted. ASTA Z 7557 had a slight advantage in cure rate over cyclophosphamide when these drugs were given i.v. or i.p. to early tumor (i.p.). However, cyclophosphamide had the advantage in cure rate when drug administration was i.v. to advanced tumor. At equimolar concentrations in vitro ASTA Z 7557 was more cytotoxic than either phosphoramide mustard or acrolein. In vivo, the activated cyclophosphamide derivatives caused some unusual toxicities at therapeutic doses that were not seen with cyclophosphamide. The toxicities manifested as spastic responses and acute deaths on rapid i.v. or i.p. injections and as chronic liver atrophies and fibrosis with i.p. treatment.

Animals↗

PubMed1984

Carbon tetrachloride-induced increase in the antitumor activity of cyclophosphamide in mice: a pharmacokinetic study.

Carbon tetrachloride is an hepatotoxin that depresses hepatic microsomal cytochrome P-450 and other enzyme activities. Cyclophosphamide is an anticancer drug that is activated by hepatic microsomal cytochrome P-450, while the products of cyclophosphamide metabolism by cytochrome P-450 can be metabolized by other hepatic enzymes. Carbon tetrachloride pretreatment has been found to increase the in vivo antitumor activity of cyclophosphamide against murine leukemia P-388. Carbon tetrachloride did not, however, affect the direct cytotoxicity of cyclophosphamide or 4-hydroxycyclophosphamide to cells in culture. Pharmacokinetic studies in mice revealed a delayed plasma disappearance of cyclophosphamide after carbon-tetrachloride pretreatment with an apparent initial half-time of 20.4 min compared to 9.0 min in non carbon-tetrachloride-pretreated mice. Plasma levels of total alkylating activity and plasma 4-hydroxycyclophosphamide increased more slowly and reached a lower peak, but were maintained for a longer time period in mice pretreated with carbon-tetrachloride than in untreated mice. The half-life for plasma elimination of 4-hydroxycyclophosphamide in untreated mice was 12 min and in carbon-tetrachloride-pretreated mice 27 min. There was, however, no difference in the area under the curve for either plasma total alkylating activity or plasma 4-hydroxycyclophosphamide between the two groups. It is suggested that prolonged exposure of tumor cells to 4-hydroxycyclophosphamide might be responsible for the increased antitumor activity of cyclophosphamide following carbon-tetrachloride pretreatment.

Animals↗

PubMed1980

Does acrolein contribute to the cytotoxicity of cyclophosphamide?

To determine whether the release of acrolein from oxazaphosphorinane-cytostatics contributes to their cytotoxic action, the effect of 4-hydroperoxycyclophosphamide, 4-hydroperoxy-semi-cyclophosphamide, 4-hydroperoxy-dechloro-cyclophosphamide, and acrolein on murine L 1210 leukemia cells in vitro was compared by measuring the median survival time (MST) after transplantation of the tumor cells in DBA2/Han mice. We found that only 4-hydroperoxycyclophosphamide, which is able to release both acrolein and the alkylating metabolite phosphoramide-mustard, decreased the transplantability of L 1210 cells, while the structurally analogous 4-hydroperoxy-dechloro-cyclophosphamide and 4-hydroperoxy-semi-cyclophosphamide, which under physiological conditions only release acrolein but no alkylating split products showed no cytotoxicity. Acrolein itself showed only a marginal effect, when administered in concentrations equivalent to the release of acrolein from the oxazaphosphorinane-derivatives in test. In this case, however, significant lysis of the L 1210 cells was observed by estimating dye exclusion, while acrolein released intracellularly from 4-hydroperoxy-oxazaphosphorinane-compounds did not. This points to a different mechanism of the cytotoxic action of extracellular acrolein and acrolein released intracellularly from activated oxazaphosphorinane-compounds. The results suggest that the cytotoxic effect of activated cyclophosphamide is based on the alkylating moiety of the molecule. Neither the 4-hydroperoxy-group nor the activated oxazaphosphorinane-ring itself, nor acrolein released intracellularly during toxification of activated cyclophosphamide exert a direct cytotoxic effect. Thus, the release of acrolein from activated CP apparently does not contribute to the cytotoxicity of CP in vivo.

Acrolein↗

PubMed1991

Myocardial toxicity of high-dose cyclophosphamide in rabbits treated with daunorubicin.

The present study was performed to evaluate experimentally the possible cardiotoxicity of high doses of cyclophosphamide after pretreatment with anthracyclines, a regimen used prior to bone marrow transplantation. A total of 27 rabbits received daunorubicin at a dose of 2.25 mg/kg per week for 10 weeks. At 1 week after the last daunorubicin dose, 13 of these rabbits received cyclophosphamide at 100 mg/kg per day x2 (total dose, 200 mg/kg). All animals were killed after 1 additional week. Seven rabbits received cyclophosphamide at 100 mg/kg per day x2 and two animals were given 50 mg/kg per day x2 without additional treatment. In all, 18 untreated rabbits served as controls. At 3 h before the animals were killed, they received [99mTc]-pyrophosphate i.v. Myocardial isotope activity was determined using a detector, and cardiac specimens were examined with a gamma-camera. Cardiotoxic effects were evaluated by myocardial isotope accumulation and pathologic changes were determined by morphology and by light and electron microscopy. The pathologic evaluation showed more frequent and widespread acute myocyte necrosis in daunorubicin/cyclophosphamide-treated rabbits as compared with those treated with daunorubicin or cyclophosphamide only. Myocardial isotope accumulation in rabbits treated with daunorubicin/cyclophosphamide was significantly higher then that in animals treated with either drug alone (2 alpha less than or equal to 0.001). Rabbits receiving cyclophosphamide as a single agent showed minor myocyte lesions but did not differ from controls in terms of isotope accumulation. We conclude that high-dose cyclophosphamide treatment on a dose schedule similar to that used prior to bone marrow transplantation and given soon after long-term daunorubicin therapy is considerably cardiotoxic.

Animals↗

PubMed1989

Haematological recovery following high-dose cyclophosphamide with autologous bone marrow transplantation.

A total of 31 patients with previously untreated small-cell carcinoma of the lung were treated with very-high-dose cyclophosphamide, using autologous bone marrow transplantation (ABMT) to assist haematological recovery. The period of neutropenia was shorter with 40 mg/kg cyclophosphamide x 4 (7 patients) than when the dose of cyclophosphamide was increased to 50 mg/kg x 4 (11 patients), despite ABMT 2 days after chemotherapy in each group. In all, 13 patients were treated with 50 mg/kg cyclophosphamide x 4, with infusion of bone marrow delayed to day 4, 6 or 8 after chemotherapy to determine the contribution of ABMT to haematological recovery. The period of neutropaenia was increased when marrow was returned 6 days following chemotherapy, confirming that ABMT contributed to haematological recovery after this schedule of treatment. A total of 11 patients had a second cycle of 50 mg/kg cyclophosphamide x 4 after recovery from the first cycle of high-dose chemotherapy. The period of myelosuppression was greater with the second cycle of chemotherapy, although ABMT was carried out during both cycles. The results show that ABMT contributes to haematological recovery when the dose of cyclophosphamide is high enough to produce prolonged hypoplasia. The increased myelosuppression observed after a second high-dose treatment in spite of ABMT suggests either that both transplanted and endogenous marrow activity contribute to recovery of myelopoiesis or that there is residual damage to marrow stroma after the first cycle of treatment. The data indicate the necessity of carefully assessing the role of ABMT in haematological recovery with high-dose chemotherapy regimens.

Blood↗

PubMed1992

Effector molecules from antitumor macrophages induced with OK-432 and cyclophosphamide.

The present study was designed to determine whether antitumor activity of macrophages induced with OK-432 and cyclophosphamide was mainly dependent on their ability to produce a soluble factor, that is, L-arginine-dependent nitric oxide as measured by nitrite concentration. Nitrite production by peritoneal macrophages from NIH Swiss mice pretreated with OK-432 (125 KE/kg) i.p. twice at 1-week intervals and with cyclophosphamide (200 mg/kg) i.p. 2 days before the second OK-432 treatment, increased with time for 24 h, and proportionally depended on macrophage numbers. Nitrite production was inhibited by actinomycin D and puromycin but not by mitomycin C. NG-Monomethyl-L-arginine, a specific competitive inhibitor of L-arginine-dependent nitric oxide synthesis, also inhibited production. There was a close correlation between nitrite production and antitumor activity in macrophages from mice pretreated with either OK-432 and cyclophosphamide, OK-432, or thioglycolate broth. OK-432 increased both nitrite production and antitumor activities when added to the macrophage from mice pretreated with OK-432 but not with thioglycolate broth. Both activities of macrophages from mice pretreated with OK-432 and cyclophosphamide were enhanced with increasing concentrations of L-arginine (0.125-1 mM) in the culture medium. D-Arginine, however, did not substitute for L-arginine. Neither activity was affected by contact between the macrophage and the EL4 cell. The macrophage showed antitumor activity through a membrane filter though the activity was greatly reduced. This antitumor activity of macrophages through a membrane was also inhibited by NG-Monomethyl-L-arginine, and increased by OK-432. However, conditioned media, obtained by culturing macrophages induced with OK-432 and cyclophosphamide, inhibited growth of EL4 cells. This activity was carried out by dialysable and non-dialysable factors. One of the dialysable factors was nitrite, an oxidized product of nitric oxide. The antitumor activity of non-dialysable factors was heat-stable and production of factors was increased by NG-Monomethyl-L-arginine and OK-432. Also, non-dialysable factors increased both antitumor and nitrite production activities of OK-432-elicited macrophages, when incubated with factors. Such activity of factors was also heat-stable. The production of factors increased with incubation time of macrophages, and was not inhibited by NG-Monomethyl-L-arginine. These results indicate that in vitro antitumor activity of macrophages induced with OK-432 and cyclophosphamide was mainly dependent on L-arginine-dependent nitric oxide, and that macrophage-associated soluble factors other than nitric oxide were also needed to inhibit fully tumor growth in vitro.

Animals↗

PubMed2003

Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes.

Several-fold differences have been observed among patients in the biotransformation of cyclophosphamide. The aim of this study was to investigate the contribution of CYP2C9 and CYP2C19 and their polymorphisms to the variability of cyclophosphamide activation. The formation of 4-hydroxycyclophosphamide was studied in microsomes from a total of 32 different genotyped human livers, as well as in yeast microsomes expressing different genetic variants of CYP2C9 and CYP2C19. The kinetic data obtained in the yeast system revealed that the intrinsic clearance (V(max)/K(m)) of cyclophosphamide by CYP2C9.2 and CYP2C9.3 samples was approximately threefold lower than that by CYP2C9.1. However, in liver microsomes, there were no statistically significant differences in the intrinsic clearance of 4-hydroxycyclophosphamide formation between the group of seven CYP2C9*1/*1 livers and the remaining nine with one or two variant CYP2C9 alleles ( P>0.7). We found a statistically significant correlation ( r(s)=0.65, P=0.003) between 4-hydroxylation of cyclophosphamide and 5'-hydroxylation of R-omeprazole, a measure of CYP2C19 activity in human liver microsomes ( n=19). No correlation was found between 4-hydroxylation of cyclophosphamide and the formation rate of hydroxycelecoxib, mainly catalysed by CYP2C9 ( r(s)=0.17, P=0.55, n=32). In conclusion, based on the correlation with the formation of R-5'-hydroxyomeprazole, CYP2C19 may partly contribute to the bioactivation of cyclophosphamide in human liver microsomes, while the role of CYP2C9 appears minor.

Antineoplastic Agents, Alkylating↗

PubMed2001

The antimetastatic effect of a single low dose of cyclophosphamide involves modulation of galectin-1 and Bcl-2 expression.

We have demonstrated that a single low dose of cyclophosphamide has an antimetastatic effect on lymphoma (L-TACB)-bearing rats by modulating the host immune response. Galectin-1, a member of the galectin family with specificity for beta-galactosides, has potent immunomodulatory properties by regulating cell-matrix interactions and T-cell apoptosis. Since galectin-1 is expressed by highly metastatic tumors, in the present study we investigated the participation of this beta-galactoside-binding protein in cyclophosphamide-induced immunomodulation. Inbred " e" rats were s.c. challenged with L-TACB. After 14 days, half of the animals received an i.p. injection of cyclophosphamide (10 mg/kg), and on day 21 tumors and spleens were excised. Cell extracts were prepared and galectin-1 expression was determined by Western blot analysis and correlated with Bcl-2 expression levels and the DNA fragmentation profile. Expression of galectin-1 was significantly decreased in tumors from cyclophosphamide-treated rats compared to non-treated rats. The same effect was observed regarding expression of Bcl-2 by tumors. In contrast, expression of Bcl-2 was significantly higher in spleens from treated animals than in non-treated rats. This effect correlated with a decreased intensity in the pattern of DNA fragmentation of spleen cells from cyclophosphamide-treated animals. Our results suggest that a single low dose of cyclophosphamide modulates the expression of galectin-1 and Bcl-2 by tumors, which could in turn influence the apoptotic threshold of spleen mononuclear cells. This mechanism could explain, at least in part, the antimetastatic effect evidenced in our tumor experimental model.

Adjuvants, Immunologic↗