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Cytotoxicity of Hyperthermia Combined with Bleomycin or cis-Platinum in Cultured RIF Cells: Modification by Thermotolerance and by Polyhydroxy Compounds¹

Division of Hematology/Oncology, Department of Medicine, and Department of Radiology, Veterans Administration Medical Center and University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

The effect of thermotolerance and of polyhydroxy compounds on the cytotoxicity of bleomycin and cis-platinum was studied in cultured RIF tumor cells. Cell survival in response to drug-heat treatments was compared in cells not previously exposed to hyperthermia and in preheated cells that had developed thermotolerance. Since cellular accumulation of polyhydroxy compounds is a potential mechanistic basis of thermotolerance, we also compared cell survival of thermotolerant cells and chemically heat-protected cells. The cytotoxicity of bleomycin and cis-platinum in control cells treated with drug plus heat (43°C, 1 h) was increased synergistically over the cytotoxicity of drug and heat alone. In thermotolerant cells, the synergistic interaction was largely reversed with the bleomycin-heat combination but retained with cis-platinum at 43°C. In the absence of heat, bleomycin and cis-platinum showed similar cytotoxicity in control and thermotolerant cells. The addition of heat protectors (erythritol or galactose) modified the drug-heat cytotoxicity similar to thermotolerance. The synergistic interaction of bleomycin-43°C, but not cis-platinum-43°C, was reversed by the polyhydroxy compounds.

¹ This investigation was supported in part by a grant from the Medical Research Service of the Veterans Administration, Washington, DC, and USPHS Grant CA-35689 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology 111K, John L. McClellan VA Medical Center, 4300 West Seventh Street, Little Rock, AR 72205.

Received 7/ 9/85. Revised 11/27/85. Revised 1/15/86. Accepted 1/16/86.