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Thermal Enhancement of DNA Damage in Mammalian Cells Treated with cis-Diamminedichloroplatinum(II)¹

Department of Physics, The University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Houston, Texas 77030

The cytotoxic effects of cis-diamminedichloroplatinum(II) (cis-DDP) were shown to be strongly potentiated by hyperthermia. The molecular mechanisms responsible for this potentiation were investigated by assaying the degree of DNA crosslinking produced under the different drug treatment conditions by the technique of alkaline elution. The results showed that the cells treated with the drug at 43° had a greater amount of DNA cross-linking immediately after treatment than did cells treated with the drug at 37°, indicating a possible thermal enhancement of drug uptake by the cells. Whereas the hyperthermia potentiated the cytotoxicity of cis-DDP by a factor of nearly 10, the degree of DNA cross-linking was only enhanced by a factor of 6.5, suggesting that while a large portion of the enhanced cytotoxicity may be attributed to the increased crosslinking other factors may also play some role. The possible influence of hyperthermia on the repair of the DNA damage induced by cis-DDP was investigated; however, no significant difference in the rate of disappearance of cross-links between cells treated at 37 or 43° was observed. Advantageous combination of chemotherapy with cis-DDP and hyperthermia for the treatment of cancer is implied by these results.

¹ This study was supported in part by the Department of Health, Education, and Welfare, NIH, National Cancer Institute Grants CA 04484, CA 23270, and CA 17891.

Received 2/13/79. Accepted 1/ 2/80.