Amifostine as a protector against cisplatin-induced toxicity in nude mice

Abstract

The mechanisms mediating the protective effects of amifostine on cisplatin-induced toxicity were investigated in tumor-bearing nude mice by quantitative immunohistochemistry for analysis of cisplatin-DNA adduct levels in tumors and kidneys. The mice were treated with cisplatin 5 or 10 mg/kg i.p. with or without amifostine 200 mg/kg 30 min prior to cisplatin. Toxicity was noted in terms of mortality and changes in body weight. Mortality was similar in the four treatment groups, regardless of cisplatin dose or whether amifostine was added or not. At a cisplatin dose of 5 mg/kg, amifostine did not affect the moderate decrease in body weight. Cisplatin 10 mg/kg alone gave a significant loss of body weight, with the nadir on day 7. By adding amifostine to 10 mg/kg cisplatin the weight loss was much less pronounced. Tumor growth was significantly more retarded among animals treated with 10 mg/kg cisplatin alone compared with amifostine + cisplatin 10 mg/kg. There was no difference in tumor growth retardation between cisplatin 5 mg/kg alone or in combination with amifostine. The most likely explanation was that the pronounced tumor growth retardation with 10 mg/kg cisplatin alone was due to the decline in the general condition of the animals rather than increased antitumoral activity per se. Analysis of cisplatin-DNA adducts in tumors showed no difference whether cisplatin 10 mg/kg was combined with amifostine or not. In kidneys there were significantly fewer tubular cells with very high adduct levels in animals pretreated with amifostine.