The Evaluation of Thermal Cisplatin Sensitization in Normal and XP Human Cells Using Mild Hyperthermia at 40 and 41 °C

The effect of protracted mild hyperthermia treatment at 40 and 41AEC given, concurrently with cisplatin, was evaluated in human normal AG1522 and human mutant XPA cells. While mild hyperthermia itself for up to 6 hours showed little to no toxic effects, it did result in significant sensitization of response to cisplatin treatment. Sensitization for the normal and mutant cell line was comparable, indicating that nucleotide excision repair (NER) probably does not have a role in this process. For the 41AEC heating, thermotolerance developed and heating times greater than 4 hours resulted in protective effects from cisplatin cytotoxicity. This was not observed for heating at 40AEC for up to 6 hours. Cisplatin is a chemotherapy agent that is widely used in the treatment of cancer and is also used in combination with other treatment modalities (1-10). A number of studies have shown that the response of cells to cisplatin can be influenced by their ability to repair cisplatin damage, and repair systems such as nucleotide excision repair (NER) and homologous recombination repair have been demonstrated to influence cisplatin sensitivity (11-16). Thus, the modulation of cellular repair pathways might influence the response to cisplatin. Many studies have shown that hyperthermia can inhibit cellular recovery and DNA repair after irradiation (17, 18). It was also shown that mild protracted hyperthermia was more effective in sensitizing cells to protracted radiation treatment due to a greater effect on cell damage accumulation and inhibition of its repair (19). Hyperthermia has already been shown to be a good sensitizer for cisplatin treatment (20-26). We also showed that hyperthermia combined with cisplatin and radiation resulted in enhanced inhibition of sublethal damage repair (27). These findings have led us to evaluate the effect of mild hyperthermia on concurrent low dose cisplatin treatment to determine if this would be a more effective treatment due to the inhibition of damage repair by hyperthermia. In addition, we used two human cell lines, one with no known repair deficiencies and the other deficient in NER (28), to determine if the thermal sensitization by concurrent protracted treatments would be influenced by a deficiency in NER.