Experimental Approaches to Reducing Platinum Induced Kidney Toxicity

Abstract

The kidney is the critical organ involved with cisplatin (DDP) pharmacology; it plays a major role in drug excretion, in platinum accumulation, and it represents the primary target for dose-limiting toxicity (1). Numerous strategies have been developed to reduce this toxicity. Hydration-diuresis regimens are now a standard component in most clinical protocols, and pharmacologic approaches designed to alter renal transport or accumulation of cisplatin or its toxic metabolites have also been explored. More recently, attention has focused on the development of agents that will react with and inactivate the toxic species involved. Most of these chemoprotectors contain a nucleophilic sulfur moiety, based upon the high affinity of sulfur containing ligands for platinum complexes. However, the reaction of platinum drugs or their metabolites may also inhibit the cytotoxic reaction in the tumor cell, thus diminishing the antitumor effect. Currently the most promising inhibitors of cisplatin-induced nephrotoxicity are WR-2721, thiosulfate, and diethyldithiocarbamate (DDTC). These agents are anionic, hydrophilic, and either possess or can generate a highly reactive sulfur nucleophile (Fig. 1). All three drugs can be administered under conditions where nephrotoxicity is diminished without apparent reduction in antitumor effect.