Cellular heat sensitivity can be modulated by prior heat or cold exposures. After an exposure to sublethal hyperthermia, cells develop thermotolerance which is characterized by a reduction in the slope of the 45C-hyperthermia survival curve by up to six fold. We have recently shown that thermotolerance can also be induced chemically at 37 C and that the development of thermotolerance can be inhibited by analogues of nicotinamide. The biochemical mechanisms of these effects are unknown. We have also shown that cellular sensitivity to heat can be reduced when either polyols or selected sugars are added to the culture medium prior to hyperthermia. Based on these observations we postulate that cellular thermotolerance is mediated by elevated levels of naturally-occurring, intracellular polyhydroxy compounds. We propose to test this hypothesis directly using gas chromatographic techniques for the quantitation of intracellular sugars and polyols along with measurements of cell survival and the levels of coenzymes required for polyol synthesis. These measurements should indicate whether heat-induced, chemically induced thermotolerance are sugar-mediated tolerance and based on the same mechanism. In addition, this study is intended to characterize and quantitate chemical induction of thermotolerance, the effects of inhibitors of glucose transport, of aldose reductase, and of thermotolerance development by nicotinamide analogues in terms of cell survival and polyol metabolism. Similarly, conditions that are known to sensitize to cellular heating killing and are considered important to the heat response of tumors in vivo (low pH, nutrient deprivation, and step-down heating) will be studied in relationship to the same endpoints. Direct experimental support for the hypothesized mechanism of thermotolerance could provide a conceptual framework for future studies in thermal biology by which apparently unrelated cellular heat effects can be understood in terms of carbohydrate metabolism. These results have application to cancer therapy possibly through the development of new methods for measuring thermotolerance in vivo and through the design of better fractionation protocols based either on hyperthermia alone, or its use as an adjuvant to conventional therapies.
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