Hyperthermia is being used as a method for cancer treatment either alone or in combination with surgery, durgs or radiation. Detailed knowledge of heat killing mechanisms is important for planning the interaction of heat with those treatments and also because thermal resistance can be induced by heating. The mechanism(s) of heat killing and induced thermal resistance are unknown, but heat """"""""shock"""""""" or """"""""stress"""""""" proteins have recently been suggested to have a role in survival following heat stress, and their induction could be related to induction of thermal resistance. The role of hyperthemic stress proteins in survival and function of tumor and endothelial cells during thermotolerance will be studied in the Fisher 344 rat and its 13762NF mammary adenocarcinoma.
The specific aims for the proposal are (1) to show stress protein synthesis in adenocarcinoma and endothelial cell lines during continuous heating 42 degrees and after a single 45 degrees heat treatment (conditions which induce thermal resitance); (2) to decide if such protein synthesis has a survival function (i.e., Are proteins synthesized under the above conditions correlated with induced resistance to continued or subsequent heat stress?); (3) to ask if this stress protein synthesis is different for the tumor versus endothelial cells and if there are differences between tumor cell clones which differ in thermal resistance; (4) to ask whether these stress proteins are specific for heat or general for stress survival; and (5) to determine the biochemical charateristics of these stress proteins and their location and function. Some of the general methodologies used to accomplish the specific aims will be water bath heating of cells, cell survival analysis, cell surface biochemistry, electrophoresis and other techniques of protein analysis, metabolic and chemical labeling, flow cytometry, antibody binding, and in vitro culture of tumor and normal cell lines and clones. Learning more about the mechanism(s) of induced thermal resistance and the role and function of stress induced proteins will be of practical clinial interest and contribute to understanding how normal and tumor cells respond to stresses induced by therapeutic agents.
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