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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.

Type

Journal article

Journal

Cancer Res

Publication Date

15/04/1996

Volume

56

Pages

1727 - 1730

Keywords

Alkyl and Aryl Transferases, Animals, Apoptosis, Cell Line, Transformed, Cell Survival, Cell Transformation, Neoplastic, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Embryo, Mammalian, Enzyme Inhibitors, Farnesyltranstransferase, Fibroblasts, Genes, myc, Genes, ras, Kinetics, Methionine, Radiation-Sensitizing Agents, Rats, Transfection, Transferases, Urinary Bladder Neoplasms