The objective of this proposal is to study the role of cell and membrane lipid composition on the response of tumor cells to hyperthermia and to one form of chemotherapy. In previous experiments we have observed that thermotolerance can be induced in the L1210 murine leukemia cell by a gradual heating process. Since this technique affords the opportunity to alter thermal sensitivity in an incremental manner, one can use it to study the mechanism of thermotolerance and the mechanism of heat killing. In this regard we propose to further characterize this process and to expand our previous studies of the role of membrane lipids. We will correlate heat sensitivity in this system with the presence of heat shock protein. We will examine the influence of prior membrane fatty acid modification on the ability to develop thermotolerance since it affects thermal sensitivity. Furthermore, we will determine the role of intracellular pH in thermotolerance and heat sensitivity since there is evidence for a major role of intracellular proton concentration in cellular proliferation and in heat sensitivity. The ability of a membrane fluidizing drug, procaine, to synergize with heat will be explored as a means of further implicating the membrane. In a second aspect of the application, we propose to further characterize our recent observation that the sensitivity of neoplastic cells to anthracycline drug is markedly enhanced by increasing membrane polyunsaturation. We will attempt to determine the mechanism of this effect by studying lipid structure of the membrane and the effect of lipid polyunsaturation on adriamycin transport. Selected studies on two relevant human cell lines will also be carried out. Our long term objective is to determine the role of the-plasma membrane in experimental therapeutics.
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