Thermal enhancement of DNA damage in mammalian cells treated with cis-diamminedichloroplatinum(II).

Abstract

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 cross-linking 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 degrees had a greater amount of DNA cross-linking immediately after treatment than did cells treated with the drug at 37 degrees, 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 cross-linking 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 differnence in the rate of disappearance of cross-links between cells treated at 37 or 43 degrees was observed. Advantageous combination of chemotherapy with cis-DDP and hyperthemia for the treatment of cancer is implied by these results.