Clinical application of hyperthermia has progressed considerably in the past decade. This modality, in which tumors are heated to tempatures of 42 degrees C to 47 degrees C, has been shown to be beneficial when combined with radiation therapy or chemotherapy. Before hypoerthermia can be applied most effectively, a fundamental understanding of how heat kills cells will be needed. Despite much research and abundant theories, the mechanisms of hyperthermic killing are still not well understood. The objective of the proposed study is to elucidate the cellular and molecular mechanisms of heat killing and determine how certain chemical compounds protect cells from heat-induced damage. Of particular interest are two compounds, cycloheximide and puromycin, which are known to inhibit protein synthesis and afford cellular heat protection. Since inhibition of protein synthesis in and of itself does not necessarily provide protection, several other biochemical processes will be investigated to determine their role in thermal stabilization. These studies will consist firstly of the determination of the relationships between drug-modified protein degradation rate and drug-altered heat sensitivity. Secondly the role of ubiquitin and polyamines on heat protection by cycloheximide or puromycin will be investigated. The determination of stabilizing effects of chemical agents on isolated enzymes such as eIF-4F and intracellular environment is also part of the proposed research. Experimentation will be performed on cells growing in controlled culture conditions and on isolated subcellular systems. These studies will provide a better understanding of mechanisms of hyperthermic killing of cells and hopefully will enable us to improve the efficacy of clinical hyperthermia.
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