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Joint Center for Radiation Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts 02115
AT cells are extremely sensitive to ionizing radiation. Since the AT gene has homology to phosphatidylinositol 3 kinases (PI 3-kinases), wortmannin, a specific inhibitor of PI 3-kinase, was used to determine if PI 3-kinase activity regulates radiation sensitivity. Human and murine cells exposed to wortmannin alone did not display significant cytotoxicity. Wortmannin in combination with radiation was an effective radiosensitizer of murine NIH-3T3 fibroblasts, with a sensitizer enhancement ratio of 1.8 at 10% survival, and had a similar effect on the human tumor cell lines HeLa, SW480, and MCF-7. Wortmannin inhibited the induction of p53 DNA-binding activity by actinomycin D and radiation and blocked the transcriptional activation of a p53 CAT reporter gene by actinomycin D. Wortmannin radiosensitized both wild-type (NIH-3T3 and MCF-7) and mutant (SW480 and HeLa) p53 cells, indicating that p53 induction was not required for radiosensitization by worthmannin. The results suggest that a wortmannin-sensitive pathway, possibly involving PI 3-kinase activity, may regulate the response of the cells to DNA damage.
1 This work was supported by funds from the Joint Center for Radiation Therapy and NIH Grant CA64585 to B. D. P.
2 To whom requests for reprints should be addressed, at JF209. Dana-Farber Cancer Institute, 44 Binney Street. Boston MA 02115. Phone: (617) 632-4946; Fax: (617) 432-3779.
Received 10/ 5/95. Accepted 11/29/95.
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