Effect of carboplatin combined with whole body hyperthermia on normal tissue and tumor in rats.

The antitumor activity and normal tissue toxicity of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin) in combination with whole body hyperthermia (WBH) (41.5 degrees C, 120 min.) were examined in an F344 rat model. Carboplatin data were compared with those of cis-diamminedichloroplatinum (II) (cisplatin). At 37 degrees C, carboplatin showed minimal activity against a rat fibrosarcoma, but when combined with WBH, the antitumor effect-of the drug was greatly enhanced. The major carboplatin-induced acute toxicity at both normothermic and hyperthermic temperatures was marked hypocellularity of the bone marrow. A significant decrease in peripheral blood platelet counts was caused by the maximum tolerated doses (MTD) of carboplatin alone and with WBH. While the lethal dose of carboplatin alone caused only minimal renal damage, mild acute tubular necrosis was observed at the MTD of carboplatin with WBH, although no significant increase in blood urea nitrogen occurred. Therapeutic ratios of the combined chemotherapy and WBH modalities were calculated by comparing tumor growth response at the MTD of drug alone and drug combined with WBH. The combination of the nephrotoxic cisplatin with WBH resulted in a therapeutic ratio of only 0.8, whereas when carboplatin was combined with WBH, a value of 3.0 was obtained, representing a 3- to 4-fold increase over cisplatin in the therapeutic ratio. These data indicate that the less nephrotoxic carboplatin in combination with WBH improves therapeutic gain and may provide a more promising clinical combination for cancer treatment than cisplatin combined with WBH.