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Understanding thermotolerance is one of the major challenges of biology. Thermotolerance can affect many cellular responses to subsequent hyperthermia by factors of up to 10,000. The impact of thermotolerance on the clinical response to hyperthermia is only just beginning to be appreciated. Taking advantage of thermotolerance, or avoiding it could significantly alter the way hyperthermia is used in tumor therapy. This study is designed to test the hypothesis that protein synthesis (perhaps heat shock proteins) is required for thermotolerance development in mammalian cells, that the rate of protein synthesis at different temperatures influences the rate of thermotolerance development resulting in the "break" in the Arrhenius plot at approximately 43 degrees, that inhibition of protein synthesis by cycloheximide (CHM) will inhibit thermotolerance development, and that reduced protein synthesis at high temperature-low temperature combinations leads to the phenomenon of "stepdown" heating. The hypothesis will be tested in both G1 and S-phase cells so that cell cycle specific differences in hyperthermia response will not affect the results. This study will use Chinese hamster ovarian carcinoma (OvCa) cells and at times Chinese hamster ovary (CHO) fibroblasts in culture. Considerable preliminary information from this laboratory exists on the temperature kinetics of thermotolerance development, on the effects of 45 degrees-hyperthermia on macromolecular synthesis, and on stepdown heating in asynchronous populations. The reason for using two cell lines is that the OvCa cell is much more efficient at developing thermotolerance than CHO. The endpoints are plating efficiency, cell attachment, rate of cell division, protein synthesis, and DNA synthesis. Synchronous populations are obtained by mitotic selection. The effects of low pH, nutritional deprivation, and the addition of glycerol or lidocaine on the relationship between thermotolerance, protein synthesis and stepdown heating will be investigated. The results of this study will further define the role of protein synthesis in thermotolerance induction, development and decay; will suggest ways whereby one might differentially enhance or prevent thermotolerance development; will show the cell cycle dependency of thermotolerance development; and will provide insight on how stepdown heating may be used in regional or wholebody hyperthermia. All four results have the potential for significantly influencing the choice of sequence of different temperatures, fractionation intervals, and the addition of sensitizing or protective agents to improve therapeutic results.
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