The goal of this research is to understand the relationships between the induction and subsequent repair of the lesions produced in DNA after exposure of mammalian cells to ionizing radiation, and radiobiological factors observed at the cell or tissue level which are thought to be important to human cancer radiotherapy. These include cell recovery mechanisms, the role of O2 tension at the time of irradiation, and possible differences in radiosensitivity between tumor cells and normal cells. The approach to these questions involves testing specific aspects of these relationships in model systems, initially in DNA-repair deficient cells exposed in vitro, and then in mouse model tumors irradiated in vivo. The proposed studies are divided into 3 specific aims. The first is to isolate and characterize radiaiotn- sensitive mutant cell lines of Chinese hamster cells so that the different enzymatic pathways involved in the repair of radiaiton- induced DNA damage can be determined. The nature of the repair defects will be examined in terms of the relative ability of the mutant lines to rejoin single- and double-stand breaks. Differences in repair at the DNA level will be compared to the ability of the lines to repair sub- and potentially-lethal damage.
Aim 2 involves an identification of radiation-induced lesions in DNA and an evaluation of their role in cell killing. New modifications of the alkaline and neutral filter techniques will be used to assay changes in the spectrum of lesions induced under different oxygen tensions and examine the mutant lines from aim 1 for defects in repair of different types of strand breaks. Finally, in aim 3, possible differences in repair kinetics between proliferating and non-proliferating cells will be further characterized in bone marrow, testes and mouse mammary adenocarcinoma tumor cells irradiated in vivo using alkaline elution coupled with both fluorometric and radioactive DNA assays. Hopefully, the results of these investigations may ultimately provide knowledge useful for improving the treatment of human cancer by radiation.
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