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Increased Therapeutic Gain of Combined cis-Diamminedichloroplatinum(II) and Whole Body Hyperthermia Therapy by Optimal Heat/Drug Scheduling¹

University of Texas, Medical School at Houston, Department of Internal Medicine [H. B., F. R. S., G. N. J., J. M. C. B.] and M. D. Anderson Cancer Center, Department of Medical Oncology [Z. H. S.], Houston, Texas 77030

To maximize therapeutic gain, the timing sequence of whole body hyperthermia (WBH) and cis-diamminedichloroplatinum(II) (DDP) was examined. Normal tissue injury as well as growth of a s.c. transplanted fibrosarcoma were measured in F344 rats treated with variable schedules of WBH and DDP. Simultaneous application of DDP (2 mg/kg i.v.) with WBH (120 min at 41.5°C) resulted in severe renal injury, body weight loss, and mortality; while sequential use of the modalities caused minimal to no toxicity. DDP or WBH alone produced only minimal tumor growth delay, whereas supraadditive antitumor effects occurred with all tested schedules of DDP combined with WBH, regardless of sequence or interval between the two modalities. We designated the ratio of antitumor effect to nephrotoxicity as specific therapeutic efficacy (STE). DDP given simultaneously with WBH produced the lowest STE (0.6–1.2), which was less than or equal to either DDP (STE = 1.2) or WBH (STE = 1.5) alone. On the other hand, schedules of DDP prior to and after WBH resulted in a STE of 1.8–3.0, a supraadditive effect. These results indicate that an optimal scheduling of DDP with WBH significantly improves therapeutic gain by reducing normal tissue injury while maintaining enhanced antitumor activity.

¹ Supported by National Cancer Institute Grant ROI-CA-43090.

² On leave from Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan.

³ To whom requests for reprints should be addressed, at University of Texas, Health Science Center at Houston, Division of Oncology/Hematology, P. O. Box 20708, Houston, TX 77225.

Received 5/24/89. Revised 9/ 5/89. Accepted 9/13/89.