Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects.

Cisplatin, a heavy metal complex, is one of the most active drugs used in the treatment of a variety of cancers. One of the major limitations to the maximization of its therapeutic potential is nephrotoxicity. Several preclinical studies have shown that pretreatment of mice or rats with amifostine (WR-2721, Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) protected against nephrotoxicity induced by both single and repeated doses of cisplatin without affecting the antitumor effects of cisplatin. The preclinical evidence of amifostine's protective effects led to phase I-III clinical studies. A phase III trial was conducted in 242 women with stage III/IV ovarian cancer receiving six cycles of cyclophosphamide/cisplatin (CP) +/- amifostine. Consistent with the cumulative nature of cisplatin-induced nephrotoxicity, by cycles 5 and 6, a significantly greater proportion of patients in the control arm compared with patients in the amifostine-treated arm were not eligible to receive cisplatin as scheduled because their serum creatinine levels had failed to return to < or = 1.5 mg/dL. Amifostine pretreatment did not affect the antitumor effects of CP as assessed by response determined at second-look surgery or overall survival. Phase II trials support these findings. To date, amifostine is the only available therapy that can ameliorate the cumulative nephrotoxic effects of cisplatin without reducing antitumor efficacy.