Glioblastoma is the most common primary malignant brain tumor. No effective treatment is available and tumors progress fatally in virtually all cases. Since these tumors are nonmetastatic, control with local treatment, such as radiotherapy, should result in cure. Unfortunately, the tumors are very resistant to radiation. We are interested in identifying cellular parameters that affect the radioresistance of glioblastoma and other malignant gliomas. Thymidine kinase is a key enzyme of the cellular nucleotide salvage pathway, and is essential for conversion of thymidine to thymidine monophosphate. We have found that thymidine kinase expression is a major radioresponse determinant in rat glioma cells. Cells that lack thymidine expression are significantly more radiosensitive relative to the wild-type cells. The degree of sensitization is large, particularly at the dose levels used in fractionated radiotherapy. The difference in low dose survival can be accounted for by a marked difference in the ability of the cells to undergo repair of sublethal damage. When herpes thymidine kinase was introduced into the thymidine kinase deficient cells, radioresistance was partially restored and sublethal damage repair was also enhanced. All other radiobiological responses, including DNA double-strand break repair, potentially lethal damage repair, G2 arrest, and cell cycle distribution, appeared similar among the cell lines. These data suggest that the thymidine kinase enzyme or its cellular gene may be an excellent therapeutic target to increase radiosensitivity and, thereby, enhance the radiocurability of malignant brain gliomas. In this proposal, we will further investigate the mechanism of thymidine- kinase-dependent sublethal damage repair and cellular radioresistance in brain tumor cell lines, and explore the possibility of radiosensitizing brain tumors by inhibiting either the activity or expression of thymidine kinase. Successful completion of these cellular studies should lay the groundwork for future animal studies and possible clinical trials.
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