These studies are predicated on the hypothesis that the cellular membrane, specifically the organizational integrity of the membrane lipids, is the initial target of hyperthermia. The continuing goals of these studies are to delineate the direct or indirect response subsequent to the membrane insult which leads to cell death, to differentiate the mechanisms responsible for heat and irradiation killing and to develop protocols which enhance thermosensitivity. One test of the hypothesis is to examine the thermosensitivity of cells and tissues grown under protocols which modify in a systematic manner the lipid constituents of their membranes. The thermal and irradiation sensitivities of a series of organisms progressing in biological complexity from a fatty acid auxotroph of E. coli, K1060 to an in vivo solid tumor, the CA755 mammary adenocarcinoma transplanted to a BDF1, mouse will be studied. One protocol which varies the fatty acid supplement of the medium for the L1060 system exerts near absolute control on the biochemical make up and biophysical characteristics of the cell membrane. Another protocol utilizes variation in dietary linoleate initiate adaptive responses for the solid tumor model which tend to maintain host tissue membrane and to a lesser extent tumor membrane properties for optimal function. In this system there are protocols (e.g., local and systemic anesthetics, cholesterol inhibitors) which interfere with the diet-mediated adaptive responses in membrane composition. Falling between these extremes in biological complexity are two models, the E. coli B/r and Bs-1 and V79 and P388 mammalian cells. Each protocol includes the exhaustive analysis of membrane constitutents (phospholipid species, relative proportion, concentrations, and fatty acid patterns; protein concentration and two dimensional PAGE patterns, and when appropriate cholesterol concentration, lipopolysaccharide concentration, fatty acid pattern and microviscosity), the results of which will be examined in relation to shifts in the organisms thermal sensitivity. These models provide a means for comparing the mechanisms of hyperthermia-induced membrane-initiated cell killing and killing by irradiation. These studies of adaptive thermotolerance and hyperthermic lethality are intended to answer questions relevant to the design of clinical studies using hyperthermia.
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