The proposed studies will determine if the heat-induced changes in nuclear protein content play a role in heat-induced cell killing. The observed correlation between excess nuclear protein content and cell killing will be tested under conditions which modify the thermal sensitivity of cells. If the correlation between these parameters remains unaltered for all modifiers (or for a class of modifiers), then we will conclude that the excess nuclear proteins are part of the process by which heat kills cells. By choosing chemical modifiers of thermal sensitivity which are targeted for the plasma membrane, the cytoskeleton and the nucleus we hope to be able to elucidate the mechanism, in part for heat-induced cell killing. Extensions of this approach will include the study of the correlation between nuclear protein and cell survival for thermotolerant cells and for step-down heating. If the functional relationship between nuclear protein content and cell survival continues to hold, we will determine the feasibility of using nuclear protein content immediately following hyperthermia as an assay for effectiveness of hyperthermia in vivo. Since failure of a tumor to respond to hyperthermic treatment appears to correspond to the lowest heat dose in the tumor, a rapid assay of the uniformity and magnitude of the cellular response to hear could be of great value in predicting the outcome of that treatment. To this end we are proposing to determine if nuclear protein changes can be observed following hyperthermia in vivo and if such changes can be correlated with tumor growth delay and/or tumor cell survival.
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