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PubMed1991

Cooxidation of cyclophosphamide as an alternative pathway for its bioactivation and lung toxicity.

A single i.p. dose of cyclophosphamide produces lung cell injury and fibrosis in mice. Although cyclophosphamide is activated by the cytochrome P-450 mixed function oxidase (MFO) system, a role for this system in the development of lung injury has not been established. The involvement of other metabolic pathways, such as cooxidation via prostaglandin H synthase, in the toxicity of cyclophosphamide has not been studied. The objectives of the current study were to assess the effects of various inhibitors of MFO and prostaglandin H synthase activity on the development of cyclophosphamide-induced lung damage and fibrosis in mice, to determine whether arachidonic acid as well as NADPH could support the activation of cyclophosphamide to an alkylating metabolite, and to assess the capacity of cyclophosphamide to serve as a reducing cosubstrate. In addition, the ability of a low dose of cyclophosphamide to prevent the lung injury from a later higher dose was determined. Treatment with SKF 525A, piperonyl butoxide, or 1-benzylimidazole, followed by a single 200 mg/kg dose of cyclophosphamide, did not diminish pulmonary thymidine incorporation (an index of cell division after injury) or hydroxyproline content (an indicator of fibrosis), compared to mice treated with cyclophosphamide alone. Pretreatment with 1-aminobenzotriazole reduced the incorporation of thymidine into lung DNA on days 3 and 10, but not on day 7, and also reduced lung hydroxyproline accumulation. Treatment with indomethacin, nordihydroguiaretic acid, or aspirin prior to cyclophosphamide greatly reduced levels of pulmonary thymidine incorporation and/or hydroxyproline content, compared to cyclophosphamide alone. Low dose pretreatment with cyclophosphamide did not prevent the lung injury or fibrosis from a subsequent higher dose. NADPH supported greater production of alkylating metabolites in liver than in lung microsomes. In contrast, the arachidonic acid-supported production of alkylating metabolites was greater in lung microsomes. No NADPH- or arachidonate-supported alkylating activity was evident in lung or liver cytosol. SKF 525A and 1-aminobenzotriazole inhibited the NADPH-supported reaction in liver, but not lung, while indomethacin and nordihydroguiaretic acid inhibited the arachidonic acid-supported reaction in lung but not liver. Cyclophosphamide was a moderately active reducing cosubstrate for 5-phenyl-4-pentenyl hydroperoxide in both lung and liver microsomes. These results demonstrate that pathways in lung tissue unrelated to MFOs can metabolize cyclophosphamide to an alkylating compound and that MFO-mediated activation of cyclophosphamide may not be essential for the development of the pulmonary toxicity associated with this drug.

Alkylation↗

PubMed1984

Phase I controlled trials of WR-2721 and cyclophosphamide.

WR-2721 is an organic thiophosphate compound which in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Controlled Phase I trials of WR-2721 and cyclophosphamide were initiated to determine if WR-2721 protected against cyclophosphamide's hematologic toxicity. Fifteen patients received WR-2721 (450-1100 mg/m2) prior to cyclophosphamide (1200-1800 mg/m2) and were subsequently retreated 4 weeks later with the same cyclophosphamide dose alone. With WR-2721 pretreatment, 11/15 (73%) patients had improved WBC counts. The mean WBC increased from 1800/mm3 on cyclophosphamide alone to 2700/mm3 with WR-2721 + cyclophosphamide (p = 0.008). In 11 patients who had nadir differential counts performed, 7 (64%) demonstrated improved nadir granulocyte counts with WR-2721. The mean granulocyte count increased from 765/mm3 on cyclophosphamide to 1274/mm3 with WR-2721 + cyclophosphamide (p = 0.05). In the second trial, 25 patients received the reverse sequence: an initial dose of cyclophosphamide (1200-1800 mg/m2) alone, followed 4 weeks later by WR-2721 (450-1100 mg/m2) prior to the same dose of cyclophosphamide. With WR-2721 pretreatment, 12/25 (48%) patients had improved nadir WBC counts. The mean WBC increased from 1550/mm3 on cyclophosphamide alone to 1850/mm3 with WR-2721 + cyclophosphamide (p = 0.02), while the nadir granulocyte count increased from 449/mm3 to 844/mm3 (p = 0.001). No patient developed microscopic or gross hematuria or inappropriate antidiuretic hormone secretion. One patient developed mild thrombocytopenia. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced granulocytopenia, but the dose modification factors and degree of clinical benefit remain to be established. The current recommended WR-2721 dose for Phase II trials is 740 mg/m2 administered over 15 minutes.

Adult↗

PubMed1996

Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial.

BACKGROUND: Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis. OBJECTIVE: To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone. DESIGN: Randomized, controlled trial with at least 5 years of follow-up. SETTING: Government referral-based research hospital. PATIENTS: 82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (> 1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis. INTERVENTIONS: Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or bolus therapy with both methylprednisolone and cyclophosphamide. MEASUREMENTS: 1) Renal remission (defined as < 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of < 1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis. RESULTS: Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41% of the cyclophosphamide group, 43% of the combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11% of the cyclophosphamide group. 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in 15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group. 32% of the combination therapy group, and 7.4% of the methylprednisolone group). CONCLUSIONS: Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen.

Adult↗

PubMed1986

Increased toxicity of the antitumor drug cyclophosphamide in mice in the presence of the volatile anesthetic agent halothane.

Exposure of mice to 0.5% halothane in air, which is close to a maintenance concentration in man, after an IP dose of cyclophosphamide produced an increase in the lethality of cyclophosphamide. The LD50 (30 day) for cyclophosphamide without halothane was 251 mg/kg; with 2 h subsequent exposure to halothane it was 152 mg/kg; and with 20 h subsequent exposure to halothane it was 158 mg/kg. The median survival time of mice receiving cyclophosphamide at doses between 137 and 240 mg/kg was more than 30 days in the absence of halothane, 12 days with 2 h halothane, and 10.5 days with 20 h halothane exposure. Survival of mice was decreased irrespective of whether 2 h halothane exposure preceded or followed cyclophosphamide administration. Separation of cyclophosphamide administration and preexposure to halothane by breathing air for 1 h abolished the decrease in survival. Halothane exposure for 2 h after cyclophosphamide had no effect on the antitumor activity of cyclophosphamide. Total-body clearance of cyclophosphamide in mice exposed to halothane was 60 ml/min/kg, as against 188 ml/min/kg in nonexposed mice. No change was produced by halothane in the area under the plasma concentration-time curve over 2 h for 4-hydroxycyclophosphamide following cyclophosphamide administration. The reason for the increased lethality of cyclophosphamide in the presence of halothane could not be determined. There was no increase in leukopenia caused by cyclophosphamide and no increase in bladder toxicity, in liver toxicity, in renal toxicity, or in the penetration of cyclophosphamide into the brain. The study, together with reports of increased toxicity in patients receiving cancer chemotherapy in close proximity to general anesthesia, should alert physicians and others to the possibility of an interaction between volatile anesthetic agents and chemotherapeutic drugs.

Animals↗

PubMed1980

[Blood level and urinary excretion of activated cyclophosphamide and its deactivation products in man (author's transl)].

Blood levels and urinary excretion of cyclophosphamide and its metabolites were determined in cancer patients receiving cyclophosphamide. Activated cyclophosphamide (4-hydroxycyclophosphamide aldophosphamide) was assayed by TLC after derivatisation to stable 4-(S-benzyl)-sulfido-cyclophosphamide. Twenty minutes after injection of 10(20) mg/kg cyclophosphamide mean peak levels of activated cyclophosphamide were found to be 1.4(2.6) nmol/ml. The rate constant for biotransformation (=activation) of cyclophosphamide in man (km = 0.132 h-1) was only 1/50 of the value found in the mouse whereas the elimination rate constant of activated cyclophosphamide (ke[M] approximately 6.78 h-1) was much higher equalling that of laboratory animals. 4-ketocyclophosphamide, carboxyphosphamide, and phosphoramidemustard reached their peak levels between 4 and 6 h after cyclophosphamide injection. Increasing quantities of cyclophosphamide metabolites were bound to plasma proteins reaching a constant level after 24 h lasted for several days. Fifty per cent of those metabolites were reversibly bound to plasma proteins. Within 24 h, the cumulative excretion of cyclophosphamide and its metabolites amounted to 50% of the dose applied. The main metabolites excreted were phosphoramide-mustard and carboxyphosphamide whereas only 2% consisted of activated cyclophosphamide. The significance of the different pharmacokinetics of cyclophosphamide in laboratory animals and man for the therapeutic index is discussed.

Aged↗

PubMed1997

Induction of DNA crosslinks and DNA strand lesions by cyclophosphamide after activation by cytochrome P450 2B1.

Cyclophosphamide requires metabolic activation by cytochrome P450 to exert its genotoxic effects. Therefore in vitro studies on its mechanism of action have been limited to the use of self-activating derivatives of cyclophosphamide or to hepatocytes as an activating system. In this study we used a cell line of Chinese hamster lung fibroblasts (V79 cells), genetically engineered to express active cytochrome P450 2B1 as the sole observable cytochrome P450 (SD1 cells). An increase in DNA strand lesions (SL: DNA single-strand breaks and alkali labile sites) was observed between 0.5 and 1.5 mM cyclophosphamide (24 h incubation) which could be classified as alkali labile sites using a modified alkaline elution assay. Compared to cyclophosphamide, its active metabolite 4-hydroperoxycyclophosphamide (4-OOH-CY) was about 250-fold more effective in induction of SL. Equimolar concentrations of phosphoramide mustard (50 microM), the ultimate DNA binding metabolite of cyclophosphamide, caused only about 50% of SL compared to 4-OOH-CY. A minimum of 12 h of incubation of SD1 cells was needed for cyclophosphamide (1 mM) until SL were detectable, compared to only 2 h for 4-OOH-CY and 1.5 h for phosphoramide mustard (50 microM). DNA crosslinks were observable after shorter incubation periods than single-strand breaks (6 h for cyclophosphamide and 1 h for 4-OOH-CY and phosphoramide mustard) and were no longer detectable at incubation periods of more than 20 h. Treatment of SD1 cells with ionizing radiation only, cyclophosphamide only, and radiation plus cyclophosphamide showed that SL induced by cyclophosphamide were not repaired during incubation with fresh culture medium (24 h). However, an efficient repair of SL caused by ionizing radiation was observed and was not inhibited by cyclophosphamide. These observations give strong evidence that different types of SL were induced by cyclophosphamide and radiation. SD1 cells were able to repair the special kind of SL induced by radiation but not the SL caused by cyclophosphamide.

Animals↗

PubMed1991

Lack of ranitidine effects on cyclophosphamide bone marrow toxicity or metabolism: a placebo-controlled clinical trial.

We previously reported that cimetidine but not ranitidine significantly enhances cyclophosphamide-induced bone marrow toxic effects and the appearance of cyclophosphamide alkylating species in a murine leukemia mouse model, and we advised caution in the use of cimetidine with microsomally metabolized anticancer drugs. Both drugs have been used for the treatment of gastric complications of chemotherapy. Using a randomized, double-blind, crossover study design, we have now evaluated the potential interaction of ranitidine with cyclophosphamide in seven cancer patients, who received two courses of cyclophosphamide, one with ranitidine and one with placebo. Four patients received ranitidine in the first course, and three received placebo. Ranitidine or placebo was started 3 days before a single dose of cyclophosphamide and given for 17 consecutive days. Ranitidine or placebo was given orally (300 mg/d), and cyclophosphamide (600 mg/m2) was given intravenously with [3H]cyclophosphamide (1000 muCi). Cyclophosphamide treatment was repeated at 4 weeks plus or minus 4 days. Blood samples were collected at intervals from 5 minutes to 24 hours after cyclophosphamide treatment and analyzed by thin-layer chromatography and radioassay for the drug and its metabolites. On days 0, 7, 14, and 21 after cyclophosphamide administration, complete blood cell counts, white blood cell differential counts, platelet counts, and SMA-17 were determined. The differences in mean nadir white blood cell counts, granulocyte counts, hemoglobin levels, and hematocrit values during ranitidine versus placebo treatment were not statistically significant. In a statistical but not a clinical sense, mean nadir platelet counts were significantly lower with ranitidine. There was a statistically significant increase in area under the curve for drug concentration in plasma x time (AUC) with ranitidine as well as a statistically significant decrease in the total-body clearance rate of the cyclophosphamide molecule. However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophosphamide and phosphoramide mustard was not statistically significant. The lack of toxicologic or metabolic interaction between ranitidine and cyclophosphamide suggests that ranitidine can be used safely with cyclophosphamide.

Adult↗

PubMed2005

[Risk factors of ovarian failure in the patients with systemic lupus erythematosus receiving cyclophosphamide therapy].

OBJECTIVE: To determine the risk factors for ovarian failure after cyclophosphamide therapy in the patients with systemic lupus erythematosus (SLE). METHODS: A case-control study was conducted among 138 female SLE patients, aged 16-45, and treated with cyclophosphamide, 46 of which with premature ovarian failure were included in the case group and 92 of which without menopause after completion of induction therapy with cyclophosphamide were included in the control group. A Logistic regression model was established and step-wise selection was used to analyze different factors, such as age of initiation of therapy, marital history, childbearing history, disease activity index, accumulative dosage of cyclophosphamide, accumulative dosage of azathiopurine, and usage of traditional Chinese medicines etc. RESULTS: Univariate analysis showed that age of initiation of cyclophosphamide treatment (OR = 1.11, 95% CI = 1.06 - 1.17), SLE activity index (OR = 1.11, 95% CI = 1.06 - 1.17), duration of Trypterygium wilfordii treatment (OR = 1.26, 95% CI = 1.05 - 1.51), duration of cyclophosphamide treatment (OR = 0.16, 95% CI = 0.028 - 0.94), and marital situation were associated with ovarian failure; and multivariate analysis showed that age of initiation of cyclophosphamide treatment (OR = 1.24, 95% CI = 1.14 - 1.35), cumulative dosage of cyclophosphamide (OR = 1.13, 95%, CI = 1.05 - 1.23), and duration of treatment of Trypterygium wilfordii agents (OR = 1.36, 95% CI = 1.09 - 1.69)were significantly associated with premature ovarian failure. Only 4 cases in the case group began to receive cyclophosphamide treatment before the age of 20 and their accumulative cyclophosphamide dosage was 28.8 - 32.4 g. The median of cumulative dosage of cyclophosphamide was only 4.8 g for the 11 cases aged 40-45 in the case group. CONCLUSION: The risk factors of premature ovarian failure during the induction therapy in SLE patients include age of initiation of cyclophosphamide treatment, cumulative dosage of cyclophosphamide and duration of treatment with leigongteng.

Adolescent↗

PubMed1990

Mechanisms of cyclophosphamide action on hepatic P-450 expression.

Cyclophosphamide was administered to adult male rats (130 mg/kg, single i.p. injection) and its effects on the P-450 enzymes that contribute to the activation of this drug in rat liver were then assessed. P-450-mediated cyclophosphamide 4-hydroxylase activity in isolated rat liver microsomes decreased by approximately 70% over a 9-day period following drug treatment. This decrease was due to the loss of cytochrome P-450 form 2c (IIC11), a major contributor to cyclophosphamide 4-hydroxylation in untreated male rat liver, while the other major hepatic cyclophosphamide 4-hydroxylase, P-450 PB-1 (IIC6), was largely unaffected. The loss of P-450 2c activity did not result from a decrease in P-450 reductase or from direct inactivation of the P-450 protein by cyclophosphamide or its metabolites, but rather was due to a reduction in hepatic P-450 2c protein and mRNA levels. Hepatic P-450 2a (IIIA2) and P-450 RLM2 (IIA2) were also suppressed by cyclophosphamide treatment. Serum testosterone, which contributes to the expression of P-450s 2c, 2a, and RLM2, was severely depleted in the cyclophosphamide-treated rats; however, this loss was not the direct cause of the decreases in these hepatic P-450s, since the decreases were not reversed upon restoration of normal testosterone levels by human chorionic gonadotropin stimulation of testicular androgen production. In contrast to the suppression of these testosterone-dependent P-450s, P-450 3 (IIA1), P-450j (IIE1), and the P-450-independent microsomal enzyme steroid 5 alpha-reductase were each elevated in rat liver following cyclophosphamide administration. In contrast to P-450 3 and steroid 5 alpha-reductase, however, the elevation of P-450j protein was transient and was not accompanied by an increase in P-450j-associated hepatic microsomal aniline hydroxylase activity. In vitro experiments revealed that P-450j was severalfold more susceptible to inactivation by the cyclophosphamide metabolite acrolein as compared with P-450 3. These observations suggest that P-450j protein is induced by cyclophosphamide treatment but that the protein is inactivated by the cyclophosphamide metabolite acrolein. These findings establish that cyclophosphamide treatment can modulate hepatic P-450 activities through multiple mechanisms and in a manner that may alter P-450 metabolism of cyclophosphamide and perhaps other anticancer drugs that undergo bioactivation in the liver.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1995

Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation.

The pharmacokinetics of cyclophosphamide has been evaluated in 15 patients with metastatic breast cancer undergoing high-dose chemotherapy with alkylating agents followed by autologous bone marrow transplantation. Each patient received two courses of chemotherapy: 4 g/m2 of cyclophosphamide by 90-min infusion prior to peripheral blood progenitor cell collection (the first course) and 6 g/m2 of cyclophosphamide with 800 mg/m2 of thiotepa by 96-h constant infusion before marrow and stem cell reinjection (the second course). In the first course, plasma cyclophosphamide concentration-time data of 9 of 15 patients were fit by a one-compartment model with Michaelis-Menten saturable elimination in parallel with first-order renal elimination. The mean (SD) Vmax and Km values were 1.47 (0.89) microM/min and 575 (347) microM, respectively. The first course data of the remaining six patients were fit using first-order elimination only. In the second drug course, plasma cyclophosphamide disposition curves of 13 of 15 patients demonstrated a decline in concentration following attainment of an initial steady state. The plasma cyclophosphamide disposition data of these patients were fit by a one-compartment pharmacokinetic model, in which the decline of plasma cyclophosphamide concentration after reaching the initial steady state was modeled as being due to an increase in the clearance rate of cyclophosphamide. The mean (SD) initial and final clearance rates were 51 (16) ml/min and 106 (48) ml/min, respectively. Michaelis-Menten elimination was not apparent in the second course because the plasma concentration of cyclophosphamide was much lower. The mean renal clearance rate was 17 ml/min in the first course and 16 ml/min in the second course. Urinary excretion of cyclophosphamide accounted for 17% and 23% of the total dose administered in the first and the second course, respectively. No change in cyclophosphamide clearance rate was apparent in a patient who was taking phenytoin, but a change was present in a patient who was taking phenobarbital. A drug interaction between cyclophosphamide and thiotepa may explain the smaller initial clearance rate for cyclophosphamide during the second drug course.

Adult↗

PubMed2000

Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens.

PURPOSE: Cyclophosphamide and thioTEPA are frequently used simultaneously in high-dose chemotherapy regimens. During a pharmacokinetic study of 31 courses in 20 patients of cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide given in the combination cyclophosphamide thioTEPA carboplatin, a sharp decrease in 4-hydroxycyclophosphamide concentration was observed immediately after the start of the thioTEPA infusion. A drug-drug interaction was suspected. This putative interaction was investigated in this study. METHODS: Possible sequence dependency, due to inhibition of the formation of 4-hydroxycyclophosphamide by thioTEPA, was investigated by altering the sequence of infusion in three patients (four courses) receiving high-dose chemotherapy with cyclophosphamide (1,000 or 1,500 mg/m2 per day), thioTEPA (80 or 120 mg/m2 per day) and carboplatin (265 or 400 mg/m2 per day) in short infusions for four consecutive days. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were established. Possible inhibition of the metabolism of cyclophosphamide and thioTEPA was investigated in human microsomes. RESULTS: A striking sequence dependency of the pharmacokinetics of 4-hydroxycyclophosphamide was observed. Administration of thioTEPA 1 h prior to cyclophosphamide resulted in decreased Cmax (-62%) and AUC (-26%) values of 4-hydroxycyclophosphamide compared to those of thioTEPA administered 1 h after cyclophosphamide. In human microsomes an inhibition of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide by thioTEPA was observed at clinically relevant concentrations with an IC50 of 23 microM. No inhibition of the formation of TEPA by cyclophosphamide was observed. CONCLUSIONS: ThioTEPA strongly inhibits the bioactivation of cyclophosphamide and this may decrease both efficacy and toxicity. Our results seriously question the practice of the simultaneous continuous infusion of cyclophosphamide and thioTEPA and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis.

Pulse cyclophosphamide is more effective than prednisone alone in preventing renal failure in lupus nephritis. We undertook a randomised, controlled trial to find out whether pulse methylprednisolone could equal pulse cyclophosphamide in preserving renal function in patients with lupus nephritis, and whether there was a difference between long and short courses of pulse cyclophosphamide in preventing exacerbations. 65 patients (60 female, 5 male; median [range] age 29 [10-48] years) with severe lupus nephritis were assigned randomly to monthly pulse methylprednisolone for 6 months (25 patients), monthly pulse cyclophosphamide for 6 months (20), or monthly cyclophosphamide for 6 months followed by quarterly pulse cyclophosphamide for 2 additional years (20). Patients treated with pulse methylprednisolone had a higher probability of doubling serum creatinine than those treated with long-course cyclophosphamide (p less than 0.04). Risk of doubling creatinine was not significantly different between short and long course cyclophosphamide. However, patients treated with short-course cyclophosphamide had a higher probability of exacerbations than those treated with long-course cyclophosphamide (p less than 0.01). An extended course of pulse cyclophosphamide is more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations.

Adolescent↗

PubMedDate not supplied

Drug interaction effects on antitumour drugs (XV): Disulfiram as protective agent against cyclophosphamide-induced urotoxicity without compromising antitumour activity in mice.

The prevention of cyclophosphamide-induced urotoxicity by disulfiram was studied in mice. A single dose of cyclophosphamide (100-400 mg/kg, intraperitoneally) produced a significant dose-dependent increase in urinary bladder weight within 48 hr of treatment. Disulfiram prevented cyclophosphamide-induced bladder damage in a dose-dependent manner in mice when orally administered simultaneously with antitumour agents, but failed to diminish the acute toxicity, leukocytotoxicity and immunotoxicity of cyclophosphamide. The protective effect of disulfiram on the bladder was critically dependent on administration timing. Oral administration of disulfiram between 60 min. before and 60 min. after the injection of cyclophosphamide was found to be effective. The optimum time was simultaneous administration of both drugs. Diethyldithiocarbamate and carbon disulfide, metabolites of disulfiram, prevented cyclophosphamide-induced bladder damage when administered simultaneously with cyclophosphamide 1 to, 3 or 5 hr afterwards. Disulfiram slightly potentiated the antitumour activity of cyclophosphamide against Sarcoma 180 or EL-4 leukaemia in vivo when administered simultaneously with cyclophosphamide. In contrast, diethyldithiocarbamate or carbon disulfide did not interfere with cyclophosphamide antitumour activity when administered 3 hr after cyclophosphamide. From these preliminary studies, disulfiram appears to be a likely candidate for protection against cyclophosphamide-induced urotoxicity without compromising the therapeutic utility of the alkylating agent.

Administration, Oral↗

PubMed1989

Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis.

In a randomised, controlled study alternate day prednisolone with an initial high dose phase ("prednisolone only series") has been compared with cyclophosphamide plus alternate day low dose prednisolone ("cyclophosphamide-prednisolone series") in 43 patients with previously untreated fibrosing alveolitis (five patients had received prednisolone in minimal dosage). In the prednisolone only series prednisolone 60 mg daily was given for one month and then reduced by 5 mg a week to 20 mg on alternate days or the minimum dose to maintain early improvement. Patients in the cyclophosphamide-prednisolone series received 100, 110, or 120 mg cyclophosphamide daily (depending on body weight) plus 20 mg prednisolone on alternate days. Treatment was continued indefinitely, or changed to the alternative regimen if the patient deteriorated, failed to improve, or developed drug toxicity. For response to treatment (as judged by change in breathlessness score, radiographic appearance, and lung function) patients were classified as improved, stable, or deteriorating. Deaths from cryptogenic fibrosing alveolitis were also analysed. Improvement had occurred at one or more assessments in seven of the 22 patients in the prednisolone only series and in five of the 21 patients in the cyclophosphamide-prednisolone series. At three years, however, only two of the 22 patients in the prednisolone only series were still improved and three stable, compared with one and seven of the 21 patients in the cyclophosphamide-prednisolone series (three of the seven had stopped treatment because of toxicity). Life table analysis suggested better survival in patients in the cyclophosphamide-prednisolone series but this was not significant. At three years 10 of 22 patients in the prednisolone only series had died compared with three of 21 patients in the cyclophosphamide-prednisolone series. With death or failure of first treatment regimen as outcome there was a significant advantage to the patients having cyclophosphamide-prednisolone. This advantage was explained in part by the better lung volumes in this group on admission. After allowance had been made for total lung capacity (TLC), no other factor was predictive of outcome. Analyses of subgroups according to TLC on admission showed that patients with a TLC below 60% predicted did badly and those with a TLC of 80% or more predicted did well with both regimens. Patients with an initial TLC of 60-79% predicted did better with the cyclophosphamide-prednisolone regimen. Side effects were uncommon in both series and those due to cyclophosphamide resolved when treatment was stopped. The combination of cyclophosphamide with prednisolone may be an alternative to prednisolone alone with an initial high dose phase. Many patients, however, failed to respond to either treatment.

Adult↗

PubMed1986

WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial.

WR-2721 S-2-(3-aminopropylamino) ethyl phosphorothioic acid, is an organic thiophosphate compound that in the animal model selectively protects against the hematologic toxicity of cyclophosphamide by factors of 1.5 to 2.0. Preliminary data from our controlled phase I trial of WR-2721 and cyclophosphamide suggested that WR-2721 protected against cyclophosphamide-induced granulocytopenia. Since variable drug doses and infusion rates were used in these early studies, we initiated a controlled phase II trial using constant drug doses to establish more precisely WR-2721's level of protection. Initially, 21 patients received 1,500 mg/m2 of cyclophosphamide alone and were retreated 4 weeks later after hematologic recovery was complete with 740 mg/m2 of WR-2721 before the same dose of cyclophosphamide. With WR-2721 pretreatment, 19 of 21 (90%) patients had improved WBC and granulocyte counts. The mean WBC increased from 1,760/mL with cyclophosphamide alone to 2,500/mL with WR-2721 pretreatment (P less than .0005). The mean granulocyte count increased from 541/mL on cyclophosphamide to 1,247/mL with WR-2721 and cyclophosphamide (P less than .0005). Following cyclophosphamide administration alone, neutropenic fevers developed in three patients. No patient experienced a febrile episode following WR-2721 and cyclophosphamide administration. Platelet nadirs below 100,000/mL were only noted in two patients treated with cyclophosphamide alone. Objective partial responses were observed in four of 19 (21%) patients with measurable or evaluable disease. These data suggest that WR-2721 provides significant protection against cyclophosphamide-induced hematologic toxicity.

Aged↗

PubMed1985

Cyclophosphamide-induced depression of the antioxidant defense mechanisms of the lung.

Cyclophosphamide causes lung toxicity in a wide variety of animals, including humans. Recent evidence suggests that oxygen (O2) potentiates cyclophosphamide-induced pulmonary injury. We hypothesized that cyclophosphamide or one of its toxic metabolites, acrolein, may potentiate O2 toxicity by depressing lung antioxidant defense mechanisms. To test this, we gave rats cyclophosphamide (100 mg/kg), acrolein (5 mg/kg), or a vehicle (control) in a single intraperitoneal injection and then killed them during a 5-day study period. Excised lungs were analyzed for reduced glutathione (GSH) content, glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GSH-R), glutathione peroxidase (GSH-P), and superoxide dismutase (SOD) activities. In the lungs of cyclophosphamide-treated rats, GSH content was increased 48% (P less than 0.001) on day 2 but progressively decreased to 50% of control values (P less than 0.001) on day 5. Significant reductions (P less than 0.005) in G6PD, GSH-R, and GSH-P activities occurred on days 1-5, and SOD activity was significantly decreased (P less than 0.005) on days 4 and 5 by cyclophosphamide. In acrolein-treated rats, GSH content and GSH-R, GSH-P, and SOD activities were indistinguishable from those in controls. However, G6PD was increased (35-38%) on days 2 and 3 but returned to control values thereafter. To assess whether the cyclophosphamide-induced reduction in lung antioxidant defenses increased susceptibility to acute O2 toxicity, we gave a separate group of rats cyclophosphamide, acrolein, or vehicle, and 4 days later exposed them to 100% O2 or air at 1 atmosphere absolute. All cyclophosphamide-, acrolein-, and vehicle-treated rats survived 60 h air exposure, and all vehicle-treated rats exposed to 100% O2 survived. In contrast, all of the cyclophosphamide-treated rats exposed to 100% O2 died (P less than 0.05) within 40 h. Acrolein had no effect on survival in 100% O2. These results indicate that cyclophosphamide, but not acrolein, depresses lung antioxidant defense mechanisms, which may be responsible for increased mortality from O2 toxicity in cyclophosphamide-treated animals.

Acrolein↗

PubMed1997

Use of testosterone to prevent cyclophosphamide-induced azoospermia.

BACKGROUND: Prepubertal patients receiving chemotherapy are relatively resistant to cyclophosphamide-induced germinal cell alterations. OBJECTIVE: To study the possible protective effect of testosterone used to inhibit germinal cell activity in men who are receiving cyclophosphamide. DESIGN: Randomized, clinical trial. SETTING: University medical center. PATIENTS: 15 patients with the nephrotic syndrome who were treated with cyclophosphamide for 6 to 8 months. INTERVENTION: Five patients received daily oral cyclophosphamide, five received cyclophosphamide in monthly bolus injections, and five received monthly intravenous boluses of cyclophosphamide plus testosterone (100 mg intramuscularly every 15 days). MEASUREMENTS: Sperm counts, serum follicle-stimulating hormone levels, and serum luteinizing hormone levels were measured before, during, and after treatment with cyclophosphamide alone or cyclophosphamide plus testosterone. RESULTS: The 10 patients who did not receive testosterone became azoospermic during cyclophosphamide therapy. In only 1 of the 10 patients did the sperm count return to normal 6 months after discontinuation of therapy. Follicle-stimulating hormone levels were elevated in these patients (mean +/- SE, 19.20 +/- 1.28 IU/L in patients receiving oral cyclophosphamide and 16.04 +/- 2.22 IU/L in patients receiving intravenous cyclophosphamide alone). All 5 patients who received testosterone became azoospermic or severely oligospermic during treatment but had a normal sperm count 6 months after the discontinuation of therapy. In these patients, the mean sperm count was 45.78 +/- 3.89 x 10(6)/mL and follicle-stimulating hormone levels were normal (5.08 +/- 0.56 IU/L). CONCLUSION: Testosterone given to men before and during an 8-month cycle of cyclophosphamide therapy for the nephrotic syndrome may preserve fertility.

Adult↗

PubMed1993

Effective immunochemotherapy of human t(4;11) leukemia in mice with severe combined immunodeficiency (SCID) using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin plus cyclophosphamide.

Human mixed lineage leukemia cell line RS4;11 with the t(4;11)(q21;q23) translocation causes disseminated and invariably fatal leukemia in mice with severe combined immunodeficiency. Whereas an immunotoxin constructed from the murine anti-CD19(B43) monoclonal antibody and the plant toxin pokeweed antiviral protein (B43-PAP) has a potent in vitro anti-leukemic effect against clonogenic RS4;11 cells, its activity is further potentiated by the active cyclophosphamide congener mafosfamid. These intriguing observations prompted us to evaluate the in vivo antileukemic efficacy of combined immunochemotherapy employing B43-PAP immunotoxin plus cyclophosphamide against human t(4;11) leukemia cells in an RS4;11 severe combined immunodeficiency (SCID) mouse model system. Intravenous injections of B43-PAP or cyclophosphamide improved survival of SCID mice challenged with RS4;11 leukemia, as reflected by markedly prolonged median survival times. After intravenous inoculation of 5 x 10(7) RS4;11 leukemia cells, the median survival times were 41 days for saline-treated control mice (n = 12), 44 days for control mice treated with unconjugated B43 monoclonal antibody and PAP (n = 12), 56 days for mice treated with the control immunotoxin G17.2 (anti-CD4)-PAP (n = 6), 79 days for B43-PAP-treated test mice (n = 12), and 80 days for cyclophosphamide-treated test mice (n = 16). Notably, combined immunochemotherapy using B43-PAP plus cyclophosphamide was significantly more effective than either B43-PAP or cyclophosphamide alone. The median survival time for a total of 22 SCID mice undergoing combined immunochemotherapy with B43-PAP followed by cyclophosphamide (n = 12) or cyclophosphamide followed B43-PAP (n = 10) was > 150 days. The Kaplan-Meier estimates and standard errors of the probability of event-free survival at 5 months after inoculation of 5 x 10(7) RS4;11 cells were 21 +/- 13% for B43-PAP-treated mice, 7 +/- 6% for cyclophosphamide-treated mice, 90 +/- 10% for mice treated with B43-PAP followed by cyclophosphamide (n = 12), and 90 +/- 10% for mice treated with cyclophosphamide followed by B43-PAP (n = 10). Our results lead us to recommend that initial consideration be given to combined immunochemotherapy protocols using B43-PAP immunotoxin plus cyclophosphamide for treatment of refractory or relapsed t(4;11) leukemias.

Acute Disease↗