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Loss of p21^Waf1/Cip1 Sensitizes Tumors to Radiation by an Apoptosis-independent Mechanism¹

Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5468

Cellular checkpoints are important mediators of the response of normal cells following genotoxic damage, and interruption of these checkpoints is a common feature of many solid tumors. Although the effects of loss in checkpoint function in tumor cells are well understood in terms of cell cycle control, there is little information on their role in determining treatment efficacy in vivo. We have examined both the in vitro and in vivo responses of isogenic lines differing only in the p53-transactivated checkpoint gene, p21^Waf1/Cip1. When assayed in vitro, loss of p21 in human colon tumor cells results in a selective induction of apoptosis [Waldman, T., et al., Nature (Lond.), 381: 713–716, 1996.] but no difference in the clonogenic survival. However, when grown as xenografts and irradiated in situ, p21-deficient tumors were significantly more sensitive to radiation as assessed both by clonogenic survival and by regrowth of the tumors following treatment. These data indicate that loss of p21 results in increased sensitivity to killing by ionizing radiation that is independent of the induction of apoptosis and cell cycle arrest but that is specific to cells when they are grown as a solid tumor. These results have important implications for assessing both the genetic determinants of sensitivity to anticancer agents and efficacy of anticancer agents.

¹ This work was supported by National Cancer Institute Grants R37 CA15201 and CA64489. N. C. D. is supported by PHS NRSA training Grant CA 09302. B. G. W. is a Research fellow of the National Cancer Institute of Canada supported with funds provided by the Canadian Cancer Society.

² To whom requests for reprints should be addressed. Phone: (650) 723-5881; Fax: (650) 723-7382.

Received 8/ 5/97. Accepted 9/22/97.

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