The goal of this proposal is to determine if oxidative stress contributes to heat-induced radiosensitization in human tumor cells. The hypothesis and aims were chosen on the basis of preliminary results and published work which suggests: 1) hyperthermia causes oxidative stress, and 2) mechanisms of resistance to oxidative stress also confer resistance to heat-induced radiosensitization. The hypothesis is that heat-induced increases in prooxidant production and/or reductions in cellular antioxidant capacity contribute to heat- induced radiosensitization.
The Specific Aims will: 1) determine if heat (41 degree - 43 degreeC)- induced radiosensitization correlates with increased prooxidant production in human tumor cells. 2) determine if heat (41 degree - 43 degreeC)-induced radiosensitization correlates with alterations in cellular antioxidant capacity inhuman tumor cells, 3) determine if changes in prooxidant production or antioxidant capacity similar to those produces by hyperthermia, are capable of inducing radiosensitization in human tumor cell lines in the absence of hyperthermia, and 4) develop flow cytometric methods for assessing antioxidant/prooxidant balance in human tumor cells as a tool for determining if the above observations occur in human tumors in situ. In experiments yielding positive results, the effects of heat-induced oxidative stress on DNA damage and/or DNA repair following heat and radiation will also determined also in experiments yielding positive results, causality will be determined by inhibiting increases in prooxidant production and/or inhibiting alterations in antioxidant capacity and determining the effects on heat-induced radiosensitization. The information gathered in these studies will provide a rigorous evaluation of oxidative stress in mechanisms of heat-induced radiosensitization in human tumor cells. If oxidative stress is shown to contribute to heat-induced radiosensitization, then well characterized methods of modifying oxidative stress would become available for testing as modifiers of heat-induced radiosensitization, and provide a theoretical framework for the rational design of improved treatment protocols using this combined modality.
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