HYPERTHERMIA STUDIES WITH HUMAN-DERIVED CARCINOMA CELLS

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Clinical results indicate that hyperthermia is most effective when used in conjunction with other forms of established cancer therapy. The imminence of Phase III clinical trials creates a need for a more comprehensive understanding of heat effects in human tumors and its combined action with radiation and drugs. Established biochemical assays and single cell survival will serve as quantitative endpoints to investigate clinical aspects of hyperthermia. Primary and established cultures of human breast, lung and colon carcinoma cells will be used to evaluate fundamental aspects of thermotolerance and thermochemotherapy. A primary goal is to establish a methodology for signalling the development of thermotolerance in heat-treated cells in freshly biopsied human tumors. Elevated levels of heat shock proteins (HSP) and glutathione (GSH) will serve as the chemical expression of heat resistance. Human umbilical vein endothelial cells will be a model for vasculature in studying heat cytotoxicity and heat resistance. Human carcinoma cells from established lines will be used to study quantitative aspects of thermochemotherapy. Exponential and plateau-phase cultures will be exposed to acute and fractionated treatments of heat in combination with x-rays or chemotherapeutic agents (i.E. L-PAM, Cis-DDP and Tamoxifen). This simulates the response of cycling and slowly proliferating cells. The efficacy of heat, x-rays or drugs in killing thermotolerant cells will be established by thermotolerant ratios. Thiol depletion will be used as a strategy to reverse the protective effects of thermotolerance. Alteration of chemotherapeutic drug transport by hyperthermia will be investigated using radiolabelled drugs. Induction of thermotolerance in tumor-derived carcinoma cells and interactive studies of heat with drugs and radiation should broaden our basis for predicting the biological response of human tumors to clinical hyperthermia.