The long term goal of this research program is to gain knowledge about mechanisms which determine the radiosensitivity of mammalian cells, with particular reference to those involved in the response of stationary or very slowly proliferating cell populations to x-irradiation. The approach is a multi-faceted one, and the endpoints to be investigated include mutagenesis, malignant transformation, cell survival and the induction of DNA damage and chromosomal abnormalities. This investigation will utilize primarily human diploid cells. An ultimate objective is to gain a better understanding of the molecular basis for the various cellular effects of radiation, as such knowledge should eventually allow a more rational approach to the prevention and treatment of human cancer. A particular focus of this project is on molecular and cellular processes associated with the repair of potentially lethal damage (PLDR) in cells x-irradiated during the stationary phase of growth. The inhibition of PLDR by chemical agents such as poly-ADP-ribose inhibitors and cordycepin will be investigated in an attempt to identify agents which might be useful clinically in the treatment of human tumors with a large capacity for PLDR. The modulating effect of PLDR on mutagenesis and sister chromatid exchanges (SCE) will be studied in cells from several genetic disorders characterized by hypersensitivity to radiation in vitro including xeroderma pigmentosum and Gardner's syndrome. The effect of PLDR on the progression of x-irradiated human cells through the life cycle after release from density-inhibition of growth will be studied in normal and ataxia telangiectasia homozygotes and heterozygotes. The dose-response relationships for the induction of mutations by x-rays will be investigated in cells from several hypersensitive genetic disorders utilizing the human diploid lymphoblast and skin fibroblast mutation assays. Finally, evidence will be sought for x-ray induced mitotic recombination in human diploid fibroblasts, and for the development of specific chromosomal rearrangements during the proliferation of irradiated cells in vitro. These will be correlated with the development of transformation to anchorage independent growth.
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