Effect of diethyldithiocarbamate rescue on tumor response to cis-platinum in a rat model.
The nephrotoxic effects of cis-dichlorodiamineplatinum(II) (NSC-119875) (DDP) in female F344 rats were effectively inhibited by administration of sodium diethyldithiocarbamate (DDTC) in doses of 750 mg/kg intraperitoneally or 100 mg/kg intravenously 2 hr after administration of DDP. Rats were inoculated with mammary tumor 13762 and treated after 10 days with DDP (2.0 or 8.0 mg/kg) with or without DDTC rescue (750 mg/kg intraperitoneally or 100 mg/kg intravenously). Initial reductions in tumor size were identical with or without rescue in all experiments. High-dose intraperitoneal rescue, however, resulted in earlier relapse and more rapid progressions at both DDP doses than was observed in the absence of rescue. Low-dose intravenous rescue led to a tumor response identical to that observed without rescue. Urinary excretion of free DDTC was increased by prior administration of acetazolamide; however, this combination was more toxic to rats after DDP administration than was DDTC alone. Intravenous administration of DDTC appeared to be the most effective route for delivery of this ligand to the kidney. These results support our earlier mechanistic hypothesis and demonstrate the feasibility of inhibition of cis-platinum toxicity by DDTC without inhibition of the antitumor effect.
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D002945:Cisplatin / Q000494:pharmacology* / Q000633:toxicity*; D004050:Ditiocarb / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D051381:Rats; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; D004050:Ditiocarb; D000086:Acetazolamide; D002945:Cisplatin