Modulation of Cisplatin toxicity by glutathione.

Organ toxicity is the major limiting factor associated with chemotherapeutic treatment of malignancy. By raising the toxicity threshold of the organ to the detrimental effects of chemotherapeutic agents, larger and possibly curative doses may be administered without unacceptable side effects. Glutathione (GSH), a major nonprotein cellular thiol, participates in numerous cellular functions, including detoxification of chemotherapeutic agents. Previously, GSH was shown to protect against cisplatin-induced lethal toxicity. We find that in non-tumor bearing animals GSH injections (500 mg/kg body weight) prior to and after a single cisplatin injection (16 mg/kg) provided significant protection against the lethal effects of this drug (90% survival for GSH+cisplatin versus 35% for cisplatin alone). In addition, when GSH was given concurrently with the cisplatin, renal toxicity was markedly reduced as assessed by renal tubular dilation, tubular sloughing, and lumenal casts. When GSH was given with cisplatin no significant differences in the number of tumor cures was observed over cisplatin treatment alone; however, a small but statistically significant increase in tumor size was observed for cisplatin+GSH treated animals. Our results suggest that GSH may protect normal as well as malignant tissue and that further studies should be designed to determine a GSH dose and schedule regimen to be used with higher cisplatin dose schedules.