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

The mechanisms mediating the protective effects of amifostine on cisplatin- induced toxicity were investigated in tumor-bearing nude mice by quantitati ve immunohistochemistry for analysis of cisplatin-DNA adduct levels in tumo rs and kidneys. The mice were treated with cisplatin 5 or 10 mg/kg i.p. wit h or without amifostine 200 mg/kg 30 min prior to cisplatin. Toxicity was n oted in terms of mortality and changes in body weight. Mortality was simila r in the four treatment groups, regardless of cisplatin dose or whether ami fostine was added or not. At a cisplatin dose of 5 mg/kg, amifostine did no t affect the moderate decrease in body weight. Cisplatin 10 mg/kg alone gav e a significant loss of body weight, with the nadir on day 7. By adding ami fostine to 10 mg/kg cisplatin the weight loss was much less pronounced. Tum or 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 increase d antitumoral activity per se. Analysis of cisplatin-DNA adducts in tumors showed no difference whether cisplatin 10 mg/kg was combined with amifostin e or not. In kidneys there were significantly fewer tubular cells with very high adduct levels in animals pretreated with amifostine.