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Therapeutic Efficacy of Cyclophosphamide as a Function of Its Metabolism¹

Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

Experiments were designed to investigate the metabolism of cyclophosphamide in vitro and in vivo following the administration of known stimulators and depressors of rat hepatic microsomal mixed-function oxidase activity, the antitumor efficacy of cyclophosphamide as a function of its metabolism, and the toxicity of cyclophosphamide as a function of its metabolism. Regarding the metabolism of cyclophosphamide by hepatic microsomal preparations, the following observations were made. (a) Pretreatment with Phenobarbital of male and female rats and of female mice increased the rate of metabolism 7-, 23-, and 7-fold, respectively. (b) pretreatment of male rats with 3-methylcholanthrene depressed metabolism to 33% of that of controls, but similar pretreatment of female mice did not alter the rate of metabolism. (c) The K_m for cyclophosphamide metabolism by microsomes obtained from male rat liver changed from 1.39 mM to 0.57 and 0.58 mM after phenobarbital and 3-methylcholanthrene pretreatment, respectively. (d) Pretreatment of male rats with thioacetamide, morphine, or cobalt chloride depressed metabolism to 12, 48, and 8% of control, respectively. (e) Male rats bearing the Walker 256 carcinosarcoma i.m. showed a depressed ability to metabolize cyclophosphamide. In vivo cyclophosphamide metabolism in rats paralleled in vitro metabolism. Thus, at early time points, blood levels of alkylating activity were (a) increased following pretreatment with phenobarbital, (b) decreased following pretreatment with 3-methylcholanthrene or cobalt chloride, (c) decreased when the animal bore the Walker 256 carcinosarcoma i.m., and (d) lower in female compared with male rats. Walker 256 carcinosarcoma cells grown i.m. in the hindlegs of male and female rats were used to evaluate therapeutic efficacy. The dose of cyclophosphamide that inhibits tumor growth in male rats by 50% was 0.7 mg/kg. Similar median effective doses were obtained in female rats and in male rats pretreated with phenobarbital or cobalt chloride. 3-Methylcholanthrene pretreatment increased the median effective dose of cyclophophamide to 3.5 mg/kg. For estimation of the toxicity of cyclophosphamide, blood leukocyte counts were made at various intervals following injection of cyclophosphamide. Little difference in the decline of the number of leukocytes or in their subsequent return to normal levels was observed between control male rats; female rats; and phenobarbital-, 3-methylcholanthrene-, or cobalt chloride-pretreated male rats. Pretreatment with phenobarbital did accelerate leukocyte depression and also increased the magnitude of depression. In methylcholanthrene-pretreated male rats and in female rats, the magnitude of depression was somewhat less and recovery rates were somewhat altered. Administered by itself, phenobarbital, 3-methylcholanthrene, or cobalt chloride had no effect on tumor growth or blood leukocyte levels. The data demonstrate the futility of trying to improve the therapeutic efficacy of cyclophosphamide by pretreatment with drugs that alter its rate of activation. In addition, the data provide a rational basis for the ineffectiveness of such an effort.

¹ This research was supported by USPHS Grant GM 15477. Part of this material appeared in abstract form (24, 25). This is Paper 2 in, the series on "Cyclophosphamide Metabolism."

Received 7/30/71. Accepted 12/ 3/71.

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