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Cell Cycle Arrests and Radiosensitivity of Human Tumor Cell Lines: Dependence on Wild-Type p53 for Radiosensitivity¹

CRC Department of Medical Oncology, CRC Beatson Laboratories, Switchback Road, Garscube Estate, Bearsden Glasgow G61 1BD [A. J. M., P. A. V., R. B.], and Radiotherapy Research Unit, Institute of Cancer Research, Sutton SM2 5NG [G. M. R.], United Kingdom

Loss of p53 function has been shown to cause increased resistance to ionizing radiation in normal murine cells; however, the role of p53 in radioresistance of human tumor cells is less clear. Since wild-type p53 function is required for radiation-induced G₁ arrest, we measured G₁ arrest in 12 human tumor cell lines that have a wide range of radiosensitivities (surviving fraction at 2 Gy, 0.11–0.8). We observed a significant correlation between the level of ionizing radiation-induced G₁ arrest and radiosensitivity. Cell lines having G₁ arrest are more radiosensitive. There is no correlation between maximal G₂ arrest and radiosensitivity. Expression of a dominant-negative mutant of p53 (codon 143, Val to Ala) in transfectants of the radiosensitive human ovarian cell line A2780 abrogates the radiation-induced G₁ arrest. Such mutant p53 transfectants are more resistant to ionizing radiation than the parental line and vector-alone transfectants, as measured by clonogenic assays. These results support the concept that wild-type p53 function is required for sensitivity of tumor cells to DNA-damaging agents, such as ionizing radiation, and that the loss of p53 function in certain human tumor cells can lead to resistance to ionizing radiation.

¹ This work was supported by the Cancer Research Campaign (United Kingdom) and the Scottish Hospitals Endowment Research Trust.

² To whom requests for reprints should be addressed.

Received 4/26/94. Accepted 6/ 1/94.

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