Toxicologic evaluation of cis-diamminedichloroplatinum II in B6D2F1 mice.

The purpose of this study was to evaluate the toxicologic responses of mice to cis-diammine-dichloroplatinum II (cis-DDP), an established antitumor drug, and compare them to those reported in rats, dogs, and monkeys. This comparison would facilitate the continuing appraisal of the usefulness and reliability of the mouse to predict the toxicologic response to antitumor drugs in human patients. In duplicate experiments, B6D2F1 mice were treated with 8, 10, 12, and 14 mg/kg of cis-DDP in single, intraperitoneal doses. These sublethal doses corresponded to 0.4, 0.5, 0.7, and 0.8 LD50. On posttreatment days 1, 3, 6, 10, 14 or 15, and 21 or 22, groups of mice were killed and blood and other tissues were collected for hematologic (8 tests), clinical chemical (11 tests), and histopathologic (11 tissues) evaluations. Cis-DDP induced reticulocytopenia, azotemia, renal tubular necrosis and damage to the gastrointestinal epithelium with the severity being dose dependent. Hematopoietic and gastrointestinal alterations were reversible. Renal lesions were still apparent 21 days posttreatment. Although the cis-DDP doses used in this study were lower than doses used in studies with other species, the organ lesions in mice were similar to those observed in rats, dogs, or monkeys. The use of the mouse offers a number of advantages for pharmaceutical and chemical development programs, but additional data will be required to assess the overall reliability of the mouse for predicting target organs of antitumor drugs and other xenobiotics in man.