Biochemical modulation of cisplatin toxicity.

The biochemical modulation of cisplatin toxicity has contributed substantially to the safe and effective administration of cisplatin in the clinic. In most cases, however, the demonstration of clinical efficacy has preceded the understanding of mechanisms by which these agents provide protection to normal tissues. A number of protocols are now available to ameliorate cisplatin-induced nephrotoxicity; these approaches have been so successful that renal toxicity is rarely of clinical significance today. However, the dramatic escalation in cisplatin dose engendered by the use of modulators has resulted in new dose-limiting toxicities involving the nervous system and the bone marrow. Although preliminary data suggests that certain modulators may reduce these toxicities, extensive clinical trials will be necessary to substantiate the beneficial effects in the clinic. Further clinical studies will also be necessary to determine the optimum scheduling for the newer agents and to provide convincing evidence of efficacy in man. Finally, modulator combinations (i.e. DDTC and hypertonic saline) have the potential to provide the broadest coverage of normal tissue protection and appear to merit more extensive clinical investigation. Cisplatin has demonstrated remarkable clinical efficacy at currently tolerated doses; further advances in the biochemical modulation of cisplatin toxicity should provide significant therapeutic gains for this important drug in the future.