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Departments of Radiation Oncology [E. J. B., G. K., W. G. M.] and Pathology and Laboratory Medicine [R. J. M.], University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina 27599 [A. D. C.]; and Departments of Chemistry [A. D. H.] and Pharmacology [S. M. S.], University of Pittsburgh, Pittsburgh, Pennsylvania 15261
Many tumor cells have a greater resistance to ionizing radiation than their normal counterparts, suggesting that the development of drugs that can reduce that radioresistance would potentiate the efficacy of radiation therapy. Because activated H-ras expression has been shown to markedly increase radiation resistance in some transformed cells, the inactivation of H-ras would then be predicted to radiosensitize these tumor cells, while leaving normal cells unaffected. H-ras depends for activity upon farnesylation, which can be blocked by farnesylation inhibitors, including the compound FTI-277. In keeping with this prediction, inhibition of H-ras processing using FTI-277 resulted in higher levels of apoptosis after irradiation and increased radiosensitivity in H-ras-transformed rat embryo cells but did not affect control cells. These experiments suggest that farnesylation inhibitors may prove clinically useful as radiosensitizers of tumors that depend on ras function.
1 This work was supported by NIH grant CA64227 (to W.G.M.).
2 To whom requests for reprints should be addressed, at University of Pennsylvania, Department of Pathology and Laboratory Medicine, 269 John Morgan Building, Philadelphia, PA 19104.
Received 1/18/96. Accepted 2/28/96.
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