The goal of this project is to determine if cellular mechanisms of resistance to heat shock and radiosensitization following acute hyperthermia share determinants. We will test the hypothesis that determinants which confer resistance to heat-induced cell killing also confer resistance to heat-induced radiosensitization. The hypothesis will be tested in two stably heat resistant cell lines which were generated from the same parental cell line, HA-1. In one cell line, HR-1, the heat resistant phenotype is associated with elevated expression of a heat shock protein, hsc 70, while the heat resistant phenotype of the other cell line, OC-14, does not involve alterations in the expression of major heat shock proteins. The hypothesis will also be tested in CCL39 cell lines which overexpress hsp 27. The experimental Plan will proceed by accomplishing the following Aims.
Aims 1 and 2 will ascertain if heat-induced radiosensitization is modified in cell lines which are stably heat resistant with or without alterations in the expression of heat shock proteins.
Aim 3 will determine if modifications in heat-induced radiosensitization in these cells is accompanied by alterations in the levels of initial DNA damage and/or in its repair.
Aim 4 will determine if heat-induced alterations in nuclear protein binding and signal transduction pathways are determinants of heat-induced radiosensitization.
Aim 5 will determine if overexpression of hsc 70 or other molecular alterations associated with heat resistance confer resistance to heat- induced radiosensitization.
Aim 6 will develop methods to measure hsc 70 and other parameters identified in Aims 1-4 that are candidates for being determinants of heat-induced radiosensitization in clinical samples. Overall, this study will further our understanding of the interaction of hyperthermia with ionizing radiation and identify determinants which could be important in future clinical trials combining hyperthermia with radiation.
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