The continuing goal of these studies is the eclucidation of the mechanism(s) responsible for death in heated and irradiated cells. Cells whose membranes have been either chronically or acutely modified will be employed. The studies will employ bacterial cells, cells grown in culture, and both solid and ascites tumor cells grown in animals. Organization of E. coli K1060 membrane lipids will be altered by varying available unsaturated fatty acids. Membranes of such cells will be further modified by agents such as local anesthetics and survival after radiation and hyperthermia correlated with altered membrane biophysical characteristics to determine if local anesthetics enhance the interaction of radiation and hyperthermia. In particular, bacterial survival following irradiation will be studied as a function of hyperthermic temperature, to determine if we can potentiate radiation killing at temperatures below that at which hyperthermic killing occurs. In addition, we propose to study the effects of hyperthermia on protein loss from E. coli as well as protein patterns on SDS polyacrylamide gels in cells which exhibit markedly different heat sensitivities. Using an in vitro mammalian cell model, V-79 membrane lipids will be modified by growing cells in media of defined lipid composition to which specific fatty acids have been added, by in vitro addition of cholesterol to the membrane or by the presence of local anesthetics. Biochemical and biophysical parameters of cells so modified will be determined and correlated with both treatment and survival. Finally, following dietary and anesthetic modification of tumor cell lipids the post-treatment growth delay and TCD 50 will be determined in mouse tumors while attempting to minimize normal tissue reactions. It is anticipated that such studies will provide information that will improve the clinical effectiveness of hyperthermia and radiation.
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