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Hyperthermic Enhancement of Cell Killing by Mitomycin C in Mitomycin C-resistant Chinese Hamster Ovary Cells¹

Department of Radiation Oncology [K. E. W., G. C. L.], and Laboratory of Radiobiology [M. B.], University of California, San Francisco, San Francisco, California 94143

The interaction of hyperthermia and mitomycin C (MMC) was studied in wild-type Chinese hamster ovary cells and in Chinese hamster ovary cells selected for resistance to MMC. Hyperthermic potentiation of MMC activity was maximal if heating was done simultaneously, or up to 3 h following MMC exposure. Heat enhanced the effect of MMC in both drug-sensitive and -resistant cells. Dose enhancement ratios increased from 1.3–2.0 at 42°C to 2.6–3.8 at 43.5°C and were similar for all cell lines. Cellular uptake of MMC was determined by high pressure liquid chromatography. MMC uptake was similar in the drug-sensitive and -resistant cell lines at 37°C. Hyperthermia (43.5°C) increased cellular uptake of MMC by 78 and 27% in MMC-sensitive and -resistant cell lines. MMC-resistant cells were more sensitive to heat alone at 42, 43, and 44°C. The results suggest that tumor cells that have developed resistance to MMC might be treated effectively with MMC combined with heat to augment the response to MMC. Resistance to MMC may also render tumor cells more sensitive to hyperthermia.

¹ This work was supported in part by Grants CA-31397 and CA-09215 from the National Cancer Institute, Department of Health, Education, and Welfare.

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, Long Hospital, Room L-75, UCSF, San Francisco, CA 94143.

Received 8/ 6/86. Revised 11/ 6/86. Accepted 12/ 3/86.