Cell cycle arrests and radiosensitivity of human tumor cell lines: dependence on wild-type p53 for radiosensitivity
McIlwrath, A.J.; Vasey, P.A.; Ross, G.M.; Brown, R.
Cancer Research 54(14): 3718-3722
1994
ISSN/ISBN: 0008-5472 PMID: 8033090 Document Number: 425847
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 G-1 arrest, we measured G-1 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 G, arrest and radiosensitivity. Cell lines having G-1 arrest are more radiosensitive. There is no correlation between maximal G-2 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 G-1 arrest. Such mutant p53 transfectants are more resistant to ionizing radiation than the parental line and vectoralone 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.