Effect of Heating on Lethality Due to Hyperthermia and Selected Chemotherapeutic Drugs2

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Abstract
Because the rate of heating alters various cellular events associated with exposure to hyperthermia (including the rate of cell death), effect of this parameter on the cytotoxic interaction between selected anticancer drugs and hyperthermia was studied. The drugs cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea, and adriamycin at 42.4°C and bleomycin and methotrexate at 43°C were tested in Chinese hamster ovary (CHO) cells in vitro. Heating times ranged from less than 3 minutes (immediate exposure) to 3 hours. For all drugs tested, synergistic cytotoxicity was not significantly altered by heating to peak temperature over 30 minutes as compared with immediate exposure. When heating to peak temperatures was prolonged to 3 hours, however, cell killing was markedly reduced, although significant sensitization to the drug remained. This was true despite the fact that, in CHO cells, heating to 42.4°C over 3 hours produced no cell killing for up to 6 hours at that temperature. These results suggested that the mechanism(s) responsible for induced thermotolerance are probably different from those that cause cellular resistance to the cytotoxic effects of the drugs tested. These results may also partially explain the relative lack of clinical success with whole-body hyperthermia and chemotherapeutic drugs as anticancer treatment, because heating to therapeutic temperatures often requires 2–3 hours.

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