EXPRESSION OF THYMIDINE KINASE IS ESSENTIAL TO LOW-DOSE RADIATION-RESISTANCE OF RAT GLIOMA-CELLS

We have found that thymidine kinase expression is a major radiorespons e determinant in rat glioma cells. Cells that lack thymidine kinase ex pression are significantly more radiosensitive relative to the wild-ty pe cells. The degree of sensitization is large, particularly at the do se levels used in fractionated radiotherapy. The difference in low dos e survival can be accounted for by a marked difference in the ability of the cells to undergo repair of sublethal damage. When herpes thymid ine kinase was introduced into the thymidine kinase-deficient mutant c ells, radioresistance was partially restored, and sublethal damage rep air was also enhanced. All other radiobiological responses, including DNA double-strand break repair, potentially Lethal damage repair, G(2) arrest, and cell cycle distribution, appeared similar among the cell lines. These data suggest that the thymidine kinase enzyme or its cell ular gene may be an excellent therapeutic target to increase radiosens itivity and thereby, to enhance the radiocurability of malignant brain gliomas.