The objective is to describe the molecular lesions induced in mammalian cells by hyperthermia and determine which of these lesions result in cell lethality. More specifically, we wish to differentiate between heat-induced lesions which, in themselves, cause cell lethality and those which radiosensitize the cells by interacting with x-ray-induced lesions. The general aim is: to continue with the studies of heat effects on DNA replicon initiation and chain elongation in relation to a possible mechanism for induction of chromosomal aberrations in cells heated during S phase; quantify the effects of heat on the number of radiation-induced single-strand breaks and the delay and extent of rejoining when heat is combined with x-rays either before, during, or after irradiation of cells during G1 or S phase; and compare various endpoints, with emphasis on transport and ion concentrations, when cells are heated during G1 or S phase. Changes in the endpoints will be quantified as a function of time after heating, including the interval of development of thermal tolerance. A particularly important parameter to study, as an index of intracellular damage from heat, will be cellular activity of polymerase-beta because loss of its activity correlates very well with both heat killing and heat radiosensitization during both thermally tolerant and nontolerant conditions. Effects on all of these endpoints will be compared as thermal sensitivity is changed by using heat sensitizers and heat protectors. Emphasis will be placed on identifying both direct effects of heat within the cell and on modification of these effects resulting from membrane damage.
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