DRUG-INTERACTION EFFECTS ON ANTITUMOR DRUGS .15. DISULFIRAM AS PROTECTIVE AGENT AGAINST CYCLOPHOSPHAMIDE-INDUCED UROTOXICITY WITHOUT COMPROMISING ANTITUMOR-ACTIVITY IN MICE

The prevention of cyclophosphamide-induced urotoxicity by disulfirum w as studies in mice. A single dose of cyclophosphamide (100-400 mg/kg, intraperitoneally) produced a significant dose-dependent increase in u rinary 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, b ut failed to diminish the acute toxicity, leukocytotoxicity and immuno toxicity of cyclophosphamide. The protective effect of disulfiram on t he bladder was critically dependent on administration timing. Oral adm inistration 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. Diethyldithiocarba mate and carbon disulfide, metabolites of disulfiram, prevented cyclop hosphamide-induced bladder damage when administered simultaneously wit h cyclophosphamide 1 to, 3 or 5 hr afterwards. Disulfiram slightly pot entiated the antitumour activity of cyclophosphamide against Sarcoma 1 80 or EL-4 leukaemia in vivo when administered simultaneously with cyc lophosphamide. In contrast, diethyldithiocarbamate or carbon disulfide did not interfere with cyclophosphamide antitumour activity when admi nistered 3 hr after cyclophosphamide. From these preliminary studies, disulfiram appears to be a likely candidate for protection against cyc lophosphamide-induced urotoxicity without compromising the therapeutic utility of the alkylating agent.