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Protective Effect of ICRF-187 against Normal Tissue Injury Induced by Adriamycin in Combination with Whole Body Hyperthermia¹

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

The use of[(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)]propane (ICRF-187) as a protective agent against normal tissue toxicity caused by combined Adriamycin (ADR) and whole body hyperthermia (WBH; 2 h at 41.5°C) was assessed in a rat model. The effect of ICRF-187 on the antitumor response induced by the combination of ADR and WBH was also investigated in order to assess alterations in the therapeutic index of this combined therapeutic modality treatment. ICRF-187 significantly reduced ADR-mediated body weight loss, renal toxicity, and cardiomyopathy under both normothermic and hyperthermic conditions as shown by morphological and functional assays. ADR-induced neuropathy (seen only in normothermic rats) was also ameliorated by ICRF-187. Although this study did not show a pronounced effect of ICRF-187 on ADR-induced acute myelosuppression, ADR-mediated chronic anemia, leukocytosis, and thrombocytosis were reduced by ICRF-187 in both normothermic and WBH-treated rats. The effect of ICRF-187 on antitumor response was evaluated with a tumor growth delay assay using an in vivo transplantable fibrosarcoma. ICRF-187 caused no significant change in tumor growth delay induced by either ADR alone or ADR combined with WBH. Indeed, the only complete tumor regression following treatment resulted from the combination of ICRF-187 plus ADR plus WBH. Thus, ICRF-187 significantly increases the therapeutic index of the combined modality treatment of ADR and WBH by selectively reducing normal tissue toxicity without interfering with antitumor efficacy.

¹ Supported by National Cancer Institute Grant RO1-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 Hematology/Oncology, P. O. Box 20708, Houston, TX 77225.

Received 10/15/90. Accepted 4/22/91.

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