Diethyldithiocarbamate and cis-Platinum Toxicity

Abstract

Nephrotoxicity continues to be a major side effect in cisdichlorodiammineplatinum(II)(DDP) therapy. Numerous strategies have been developed in an attempt to reduce this toxicity. Intravenous prehydration with or without mannitol diuresis is partially effective and has become the mainstay of most clinical protocols (1). A variety of sulfur nucleophiles has been studied as inhibitors of DDP nephrotoxicity, including cysteine, N-acetylcysteine, cysteamine, penicillamine (2), methionine, thiourea(3), thiosulfate (4), and diethyldithiocarbamate (DDTC)(5). It is apparent that, for most of these “rescue” agents, the timing of administration is critical. Only thiourea at high doses and DDTC are effective when administered more than one hour after DDP, and of those compounds which reduce toxicity when given before or concurrent with DDP, reduced therapeutic efficacy is frequently observed. Thiosulfate, for example, is effective when given from one hour before to 30 minutes after DDP, but the ILS of mice bearing L1210 leukemia and therapeutic doses of DDP was significantly reduced by simultaneous administration of thiosulfate. Thiourea is very effective in reducing DDP-induced nephrotoxicity; its effect on tumor response to DDP, however, is highly sensitive to dose and time of administration. Thiourea has also been shown to prevent platinum-DNA crosslinks and to reverse the cytotoxicity of DDP in vitro even when administered 41/2 hours after DDP treatment (6). We have demonstrated that DDTC effectively ameliorates both nephrotoxicity and local gastrointestinal toxicity in the rat at doses as low as 100 mg/kg when administered between 1 and 4 hours after DDP. Although large doses of DDTC (7 50 mg/kg) do alter the response of rat mammary tumor 13762 to DDP, lower DDTC doses have no effect upon tumor response (5). The results described in this report provide additional evidence for DDTC’s promise as a highly selective agent for the inhibition of toxicity induced by cis-platinum.