Although ionizing radiation causes DNA damage that can play a role in tumorigenesis, such irradiation is also an important modality of cancer therapy. We studied the radiation response of the U-87 MG human glioblastoma cell line and transfected derivatives in which p53 function had been inactivated. Although little effect of p53 on the radiation sensitivity of asynchronously growing cultures could be detected, inactivation of p53 resulted in a large increase in clonogenic survival when cells synchronized by mitotic selection were irradiated in early G1. 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 excluded 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 documented the first example of a prolonged p53-dependent G1 arrest induced by ionizing radiation during the first postirradiation cell cycle of tumor cells, suggesting a role for G1 arrest in determining the sensitivity of these cells to irradiation.

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This work is supported in part by the Robert Steel Foundation for Pediatric Cancer Research and by Public Health Service Grants CA09215 and CA61019 from the National Cancer Institute to the Department of Radiation Oncology and NS31076, CA13525, and CA64898 to the Brain Tumor Research Center, University of California, San Francisco. The investigators are also appreciative of support for this research from the Betz Foundation, the Price Family Foundation, and the Preuss Foundation.

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