CELL-CYCLE SYNCHRONY UNMASKS THE INFLUENCE OF P53 FUNCTION ON RADIOSENSITIVITY OF HUMAN GLIOBLASTOMA CELLS

Although ionizing radiation causes DNA damage that can play a role in tumorigenesis, such irradiation is also an important modality of cance r therapy, We studied the radiation response of the U-87 MG human glio blastoma cell line and transfected derivatives in which p53 function h ad been inactivated, Although little effect of p53 on the radiation se nsitivity of asynchronously growing cultures could be detected, inacti vation of p53 resulted in a large increase in clonogenic survival when cells synchronized by mitotic selection were irradiated in early G(1) . The radiation dose sufficient to reduce cellular clonogenicity by 1 log in cells expressing functional p53 was 3.26 +/- 0.12 Gy, whereas a much higher dose (7.41 +/- 0.44 Gy) was required to achieve the same killing effect in cells in which p53 was inactivated. Apoptosis was ex cluded as a probable mechanism contributing to the radiosensitivity of these cells. Fluorescence-activated cell sorter analysis, continuous labeling with tritiated thymidine, and time-lapse videomicroscopy docu mented the first example of a prolonged p53-dependent G(1) arrest indu ced by ionizing radiation during the first postirradiation cell cycle of tumor cells, suggesting a role for G(1) arrest in determining the s ensitivity of these cells to irradiation.