Cisplatin chemoprotection and rescue: pharmacologic modulation of toxicity

Although cisplatin is one of the most important antitumor agents yet developed, associated toxicities continue to limit its potential usefulness. Depending on the cisplatin dose and method of administration, limiting toxicities may include nephropathy, ototoxicity, peripheral neuropathy, or even myelosuppression. Recent therapeutic strategies such as hypertonic saline have proven successful in reducing the incidence of renal insufficiency, thus allowing cisplatin dose escalation to the level of 200 mg/m2 per 28-day cycle. Unfortunately, ototoxicity and a cumulative dose-related peripheral neuropathy have recently emerged as additional dose-limiting toxicities. One method of optimizing the therapeutic index of cisplatin is the concurrent administration of chemoprotective or rescue therapy. Ideally, an effective rescue agent would selectively reduce cisplatin-related side effects without reversing its antitumor activity. Three chemoprotective agents currently undergoing evaluation--WR-2721 (ethiofos), DDTC (diethyldithiocarbamate), and ORG-2766--have demonstrated preclinical efficacy. Clinical trials now in progress suggest that each agent may offer unique advantages, but many questions remain regarding the optimal use of these agents.