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Expression of Thymidine Kinase Is Essential to Low Dose Radiation Resistance of Rat Glioma Cells¹

Departments of Radiation Medicine [I. A., Y. V., A. D., T. J. J.] and Neurosurgery [Y. T., R. M.], Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, DC 20007

We have found that thymidine kinase expression is a major radioresponse determinant in rat glioma cells. Cells that lack thymidine kinase 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 mutant 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, to enhance the radiocurability of malignant brain gliomas.

¹ This work was supported in part by a Brain Cancer Research Center Grant P20 CA60176 awarded by the National Cancer Institute, NIH, United States Department of Health and Human Services.

² To whom correspondence should be addressed, at the Department of Radiation Medicine, Georgetown University Medical Center, 3800 Reservoir Road, N. W., Washington, DC 20007-2197.

Received 5/13/94. Accepted 8/25/94.

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