The in vivo cytotoxic activity of procarbazine and procarbazine metabolites against L1210 ascites leukemia cells in CDF1 mice and the effects of pretreatment with procarbazine, phenobarbital, diphenylhydantoin, and methylprednisolone upon in vivo procarbazine activity

Abstract

An in vivo assay of the activity of procarbazine, N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride, and several metabolic intermediates against IP-implanted L1210 leukemia cells in CDF1 male mice is described. Treatment of tumor-bearing mice with procarbazine at doses of 300-500 mg/kg IP increased the mean lifespan of treated mice by 29%-32% relative to that of untreated animals. Procarbazine treatment with doses of 200-400 mg/kg/day given IP for 3 consecutive days increased mean lifespan by 39%-46%. The major circulating metabolite, azoprocarbazine (N-isopropyl-alpha-(2-methylazo)-p-toluamide), was as active as procarbazine when administered at equivalent doses for 3 consecutive days. A 2:1 mixture of azoxyprocarbazines (N-isopropyl-alpha-(2-methyl-ONN-azoxy)-: and N-isopropyl-alpha-(2-methyl-NNO-azoxy)-p-toluamide) was more active than procarbazine, increasing mean lifespan by 76% using the 3-consecutive-day dose schedule. The effects of pretreatment with procarbazine and drugs that are often co-administered with procarbazine, i.e., phenobarbital, diphenylhydantoin, and methylprednisolone, upon procarbazine anticancer activity against L1210 ascites leukemia cells was also determined. Pretreatment of CDF1 male mice with phenobarbital and diphenylhydantoin for 7 days was found to increase the antineoplastic activity of procarbazine by 13%-24%. Pretreatment with methylprednisolone did not significantly alter procarbazine activity. The effects of pretreatment with procarbazine, which is often administered daily for a period of 2-4 weeks, on procarbazine antineoplastic activity were varied. The results of these preliminary pretreatment studies combined with the finding that procarbazine metabolites have antitumor activity that is equal to or greater than that of the parent drug suggest that current clinical protocols that use procarbazine along with agents capable of altering procarbazine metabolism may involve drug interactions that alter the efficacy of procarbazine as an anticancer agent.