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Effect of Topoisomerase II Inhibitors on Hyperthermic Cytotoxicity¹

Department of Radiology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132

Exposure of HeLa or Chinese hamster ovary cells to drugs (novobiocin, nalidixic acid, or oxolinic acid) which inhibit the nuclear enzyme topoisomerase II resulted in a sensitization of both cell lines to hyperthermic heating at 41 and 45°C. Exposure to 0.5 mg/ml novobiocin decreased the reciprocal slope (T₀) of the survival curve of HeLa cells heated at 41 and 45°C by a factor of 7.5 and 2.4, respectively. Exposure to 0.5 mg/ml novobiocin decreased the T₀ of the survival curve of Chinese hamster ovary cells heated at 41 and 45°C by a factor of 9.8 and 1.8, respectively. Exposure of HeLa cells to 0.5 mg/ml novobiocin delayed thermotolerance development for 1.5 h and depressed by a factor of 27 the survival of cells heated at 45°C once thermotolerance had developed. Coincident with the sensitization to heat-induced cytotoxicity, an enhancement of a heat-induced increase in the total protein mass coisolating with the nuclei or nuclear matrices from heated cells was observed. A log-linear correlation was found between the reduction in cell survival and the relative nuclear matrix protein mass increase in cells heated at 41 or 45°C in the presence or absence of these drugs. The results are consistent with the notion that exposure to these drugs disrupts the cell's capacity to regulate nuclear structure and composition, and thus enhances heat-induced cytotoxicity.

¹ This work was supported by Grant CA-25957 from the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Department of Radiology, University of Utah Health Sciences Center, Salt Lake City, UT 84132.

Received 10/19/87. Revised 3/ 7/88. Accepted 4/14/88.