Cisplatin rescue therapy: experience with sodium thiosulfate, WR2721, and diethyldithiocarbamate

Cisplatin has a steep dose response curve for both antitumor and adverse effects. Therapeutic strategies aimed at reducing toxicity and allowing dose escalation of intravenous cisplatin, such as administration in hypertonic saline and pharmacokinetically based dosing schedules, have been partially successful in reducing nephrotoxicity and bone marrow suppression. However, new dose-limiting toxicities consisting of peripheral neuropathy and ototoxicity have emerged, which continue to restrict potential use of high dose cisplatin therapy. Intraperitoneal administration of high dose cisplatin also offers the potential of markedly increased local drug exposure if systemic toxicity can be avoided. Proposed chemoprotective agents, including sodium thiosulfate, WR2721, and diethyldithiocarbamate (DDTC) are being extensively examined as "rescue agents" for either regional or systemic administration of cisplatin. Although each agent offers unique advantages to be considered in developing successful rescue therapy, many questions remain regarding molecular and pharmacokinetic interactions with cisplatin, appropriate dosing schedules, and effects on antineoplastic activity. We present a review of current investigations of chemoprotectors for prevention of cisplatin-related toxicities.