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Increased Therapeutic Efficacy Induced by Tumor Necrosis Factor Combined with Platinum Complexes and Whole-Body Hyperthermia in Rats¹

Department of Internal Medicine [S. O., F. R. S., M. M., J. M. C. B.], University of Texas Medical School at Houston, and Section of Pharmacology [Z. H. S., A. R. K.], Section of Veterinary Pathology [L. C. S.], and Department of Tumor Biology [J. K., S. P. T.], M. D. Anderson Cancer Center, Houston, Texas 77030

This study examined the effect of a trimodality therapy of the combination of recombinant human tumor necrosis factor (TNF), wholebody hyperthermia (WBH), and cis-diamminedichloroplatinum(II) (CDDP) or cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA) on a fibrosarcoma and normal tissue in F344 rats. TNF (1 x 10⁵ units/kg) increased the antitumor effect of both CDDP (1.5 mg/kg) + WBH (2 h at 41.5°C) and CBDCA (30 mg/kg) + WBH. Tumor growth delay, which was 1.9 days for CDDP + WBH and 2.7 days for CBDCA + WBH (P < 0.01 compared to control), was significantly increased to 2.9 days with TNF + CDDP + WBH and 5.4 days with TNF + CBDCA + WBH (P < 0.05). WBH, TNF, CDDP or CBDCA alone, TNF + CDDP, TNF + CBDCA, or TNF + WBH had no significant effect on tumor growth. In contrast, administration of TNF did not enhance the CDDP- or CBDCA-mediated dose limiting normal tissue toxicity. CDDP + WBH-mediated acute renal injury and CBDCA + WBH-mediated acute myelosuppression, as determined by blood urea nitrogen and peripheral blood cell counts, respectively, were not increased with the addition of TNF to either dual modality therapy. Histopathologically, addition of TNF produced no significant alterations in the kidney and the bone marrow as compared to CDDP + WBH or CBDCA + WBH. These data show that TNF enhanced the platinum + WBH-mediated antitumor effect without increasing normal tissue toxicity, suggesting that TNF may increase the therapeutic efficacy of CDDP or CBDCA combined with WBH.

¹ Supported by National Cancer Institute Grants R01-CA-43090 and R01-CA-41581.

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

³ On leave from Department of Surgery I, Faculty of Medicine, Tottori University, Tottori 683, Japan.

⁴ 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 1/ 3/92. Accepted 5/27/92.