The objective of this research is to understand the relationships between formation and repair of lesions in DNA at the molecular level and radiobiological phenomena at the cell or tissue level which are believed to be important to human cancer radiotherapy; including cellular recovery, the oxygen effect, the increased effectiveness of high LET radiation, and differences in radiosensitivity among tumor cells and normal cells. The experiments proposed will take advantage of new model systems and other relatively new technology to help address these questions. Specifically, we propose the following: (1) to investigate the role of DNA strand break rejoining mechanisms in cell survival and in recovery from sublethal and potentially lethal damage by use of repair-deficient mutants of Chinese hamster cells and inhibitors of DNA repair. (2) to investigate the long term time course of DNA strand break rejoining in normal and tumor tissues of mice irradiated in vivo. (3) to investigate possible explanations for the observed differences in efficiency of DNA strand break production among different normal and tumor tissues of mice irradiated in vivo. This study will include (a) measurements of the strand breaks produced under different conditions of oxygenation of the tissues (b) determination of the influence of radiation sensitizers on efficiency of break formation, and (c) measurements of normal and tumor tissue glutathione levels under different conditions of oxygenation. (4) to develop appropriate models based on the results of the aims above which will satisfactorily explain the role of unrepaired DNA strand breaks in cellular lethality both in vitro and in vivo. An important aspect of our approach is the application of the alkaline elution technique to the study of DNA strand break formation and repair in normal and tumor tissues of mice irradiated in-vivo with doses of ionizing radiation in the range used for therapeutic purposes. Ultimately, we hope that this approach will yield knowledge that can be exploited for the design of better regimens for radiotherapy of human cancer.
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