ROLE OF PROGRAMMED CELL DEATH IN RADIATION RESPONSE

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The goal of this research project is to understand the mechanisms of radiation-resistance that allow tumor cells to escape the mode of cell death known as apoptosis. It is based on experiments conducted in the investigators' laboratory during the last funding period that indicated that tumors that are relatively easy to cure display substantial apoptosis whereas tumors that are relatively resistant have no apoptotic response. These results are consistent with the premise that apoptosis may play a significant role in tumor response to radiation. However, since many tumors appear to be resistant to this mode of cell death the researchers have focused on delineating the biochemical and molecular mechanisms which dictate apoptosis propensity. Two molecular pathways have been uncovered which may account for radiation-resistance through inhibition of apoptosis and these are controlled by the bcl-2 oncogene and the p53 tumor suppressor gene. The specific aims of this proposal are directed to understanding these mechanisms in more detail, exploring strategies to overcome their ability to block apoptosis, anc evaluate their possible role in the response of radiotherapy patients. Specifically the investigators propose to: (1) Determine the biochemical mechanism by which the bcl-2 oncogene regulates apoptosis propensity. (2) Evaluate strategies for modulating p53 function in an effort to enhance apoptosis in resistant tumors. (3) Examine the possible role of apoptosis in patient response to radiotherapy by retrospective analysis of pretreatment biopsy specimens. The presence of resistant cells in tumors may be a critical factor in determining the ultimate cure of patients by radiotherapy. Whereas many factors have been examined previously to measure and predict tumor cell sensitivity to radiation, the propensity for apoptosis is a relatively new endpoint. The specific aims of this project are designed to address the role of apoptosis in radiation response and may ultimately impact patient treatment by verifying that the pretreatment apoptotic index predicts response and by developing strategies for overcoming resistance due to suppressed apoptosis propensity.