Haematological toxicity of carboplatin and cisplatin combined with whole body hyperthermia in rats

Abstract

Acute haematological toxicity induced by cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin) and cis-diamminedichloroplatinum (II) (cisplatin) in combination with whole body hyperthermia (WBH) (2 h at 41.5 degrees C) was examined using a F344 rat model. The thermal enhancement ratios (TERs) of drug-mediated thrombocytopenia, anaemia and leukopenia were determined from the dose-response curves of the nadir values of the peripheral platelet, RBC and WBC counts. Carboplatin produced profound depression of platelet counts which was over three-fold greater than cisplatin (14% vs 51% of the control), while the decrease in WBC and RBC counts induced by carboplatin did not differ significantly from those observed with cisplatin. These carboplatin or cisplatin-mediated haematological toxicities were significantly enhanced by WBH. The depth of decrease in platelet, RBC and WBC counts induced by the maximum tolerated dose (MTD) of carboplatin (30 mg kg-1) combined with WBH was identical to that induced by the MTD of carboplatin (70 mg kg-1) alone. The TERs of carboplatin-mediated thrombocytopenia, anaemia and leukopenia were 2.0, 2.8 and 1.9, respectively. The thermal enhancement of cisplatin mediated haematological toxicity was similar to that of carboplatin, with TERs of 1.8 for thrombocytopenia, 2.4 for anaemia and 1.9 for leukopenia. These data, demonstrating thermal enhancement of cisplatin or carboplatin-mediated haematological toxicity, must be taken into account in the clinical application of the combination therapy of platinum and WBH.