The long-term objectives of this proposal are to (1) selectively enhance tumor thermal sensitivity by modulating the glycolysis/high-energy phosphate cycle, (2) develop the metabolic basis for and evaluate the possibility of non-invasively predicting tumor thermal sensitivity (based on indices of tumor energy status and pH), and (3) evaluate the possibility that thermotolerance decay kinetics are variable and tissue specific. Tissue specific variability in the kinetics of tolerance decay could serve as a basis for structuring hyperthermia fractionation protocols to minimize damage to normal tissue and maximize damage to tumor tissue. To accomplish these objectives, a series of experiments with normal and transformed cells will be performed under defined in-vitro conditions to (1) determine the degree of cellular coupling between, and metabolic control of, pH and cell energy status, and (2) determine the independent and interactive effect of pH (intracellular and extracellular) and energy status (e.g. ATP/Pi) on cell thermal sensitivity. The choice of these metabolites for investigation is based on in-vitro studies showing that abrupt changes in cellular ATP levels or extracellular pH markedly influence cell thermal sensitivity, and on differences in the pathways of generation and the net production of these metabolites between normal and cancer cells. Tumor cells likely differ from normal tissues not only in their capacity to regulate these metabolites, but also in their response to substrate availability and acid transport inhibitors. The tumor cells used for the in-vitro studies will also be employed for the in-vivo tumor studies. In these in-vivo studies, naturally occurring and selectively induced changes in energy status and pH will be evaluated for their tumor thermal sensitizing properties. Tissue metabolite concentrations will be determined invasively, as well as non-invasively using 31p-NMR. The existence of tissue specific and variable tolerance decay kinetics will be evaluated in various slowly or non-proliferating murine normal tissues and in more rapidly proliferating tumors. An explicit evaluation of the relationship between proliferative rate and tolerance decay kinetics will be made with model cell lines which express full contact inhibition at moderate densities, but proliferate rapidly at low cell densities.
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