heat-induced thermal resistance (thermotolerance) presents important considerations in the application of fractionated hyperthermia in cancer therapy. The long-term objective of this project is to answer the question: can thermotolerance be induced purposefully in selected normal tissue while niminizing its induction in tumor tissue, in order to maximize the therapeutic efficacy of localized herperthermia in the treatment of cancer? We plan to investigate systematically the phenomeon of thermotolerance. As part of this study, we hope to develop an assay us to determine the degree of thermotolerance existing in various tissues, both normal and malignant. This assay could conceivably be extended to the clinic. for this purpose we propose: 1. to quantify the kinetics of the development of thermotolerance in vitro and in vivo; 2. to correlate the kinetics of the development of thermotolerance with the kinetics of the synthesis of heat shock proteins; and 3. to investigate the possibility of using the quantification of heat shock proteins as a new assay both for thermal sensitivity of various tumors and normal tissues, as well as for the kinetics of thermotolerance developoment. Cellular survival will be assayed by colony formation techniques. Tumor response will be determined by in vivo/in vitro cell survival and in vivo/in vivo tumor regression/regrowth assay. The measurement of normal tissue damage will include skin reaction grading, intestinal crypt cell survival, and mouse bone marrow CFUs assay. Heat shock proteins will be identified by comparing proteins synthesized by heat-treated cells with protein synthesized by non-treated controls using SDSpolyacrylamide gel electrophoresis. The results of the proposed work will test the validity of our working hypothesis, that is, that the synthesis of heat shock proteins is causally related to the development of thermotolerance in mammalian cells and in various tissues. A positive correlation between the kinetics of synthesis of heat shock proteins would suggest using quantification of the rate of synthesis and total synthesis of heat shock proteins to predict thermal responses.
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