DNA DAMAGE IN RADIATION RESPONSE OF TISSUES AND TUMORS

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Despite the general belief that genomic DNA represents the primary. cellular target for ionizing radiation, the relationships between DNA damage and repair processes and the radiosensitivity of tumors and normal tissues remain poorly defined. This is due largely to the lack of good assays for DNA or chromosome damage in vivo and to the fact that the behavior of the target cell population in a tissue or tumor may be obscured by the response of cells that play little or no part in the biological response to radiation. The objective of this proposal is to quantitate the relationships between DNA damage and repair in various cellular subpopulations within tissues and tumors and the biological response of these tissues as measured by predominantly clonogenic assays of stem cell survival. We will investigate the relationships between DNA damage and repair in normal tissues such as bone marrow through the use of radiomodifying agents to manipulate radiation response. We will also examine several mouse tumors of varying intrinsic radiosensitivity and use radiomodifying agents to further modulate the response of these tumors. A further test system that we will study is a series of radiosensitive rodent cell lines that have a defect in some aspect of DNA repair; these lines will be grown in vivo in immune suppressed mice and assessed for their radiosensitivity and for their DNA damage and repair characteristics. A particular goal will be to expand the range of DNA lesions and chromosomal aberrations that can be measured in vivo after biologically relevant doses of radiation. We will also assess the use of flow cytometry in evaluating DNA or chromosome damage on an individual cell basis in specific cell types within tumors and normal tissues. Through this information, we hope to develop a better understanding of the relationships between DNA damage and cell death in vivo and be in a position to identify those factors (such as oxygen tension or glutathione levels) responsible for the previously described differences between cell culture systems and tissues or tumors.