Hyperthermia is finding increasing clinical potential in cancer therapy, especially when combined with chemotherapy or radiotherapy. One complication in the clinical use of hyperthermia is the ability of cells which survive an initial heat exposure to develop transient tolerance to a second heat exposure that can persist for several days. During this period, the heat-tolerant cell population may also be resistant to radiation and drug therapy. A growing body of literature suggests superoxide plays a major role in heat-induced cytotoxicity. Further, it is possible the production of superoxide in heat-shocked cells induces synthesis of antioxidant enzymes that (a) remove superoxide from the cell, making the cell resistant to increased generation of superoxide as may occur during subsequent heating, and (b) are among the heat shock proteins which are selectively synthesized after heat shock, and which may be involved in the development of thermotolerance. The role of superoxide in heat induced cytotoxicity will be studied by measuring indicators of superoxide production and superoxide damage in CHO cells after heat shock. The effect of inhibitors of the antioxidant enzymes, or of cellular superoxide production on heat-induced cytotoxicity will be investigated. Modification of heat induced cell killing by liposomal incorporation of the antioxidant enzymes catalase and superoxide dismutase into cells will also be studied. Antioxidant enzyme activities will be measured in CHO cells after heat shock, to determine if changes in the activities of these enzymes correlated with the induction and decay of heat shock protein synthesis and thermotolerance. Further, the effect of inhibitors of the antioxidant enzymes or of intracellular superoxide production on heat induced cytotoxicity of thermotolerant cells will be investigated. Catalase and superoxide dismutase will be isolated from CHO cells and the physical characteristics and proteolytic digests of these enzymes compared with the various heat shock proteins to determine if these enzymes are among the heat shock proteins. Such studies may identify the function of some of the heat shock proteins in the development of thermotolerance and provide information on the mechanism of heat-induced cytotoxicity and the development of tolerance to this toxicity could thus improve clinical protocols utilizing hyperthermia, especially if modification of the tolerance can be achieved.
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