THE FARNESYLTRANSFERASE INHIBITOR FTI-277 RADIOSENSITIZES H-RAS-TRANSFORMED RAT EMBRYO FIBROBLASTS

Many tumor cells have a greater resistance to ionizing radiation than their normal counterparts, suggesting that the development of drugs th at can reduce that radioresistance would potentiate the efficacy of ra diation 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 inh ibitors, including the compound FTI-277, In keeping with this predicti on, inhibition of H-ras processing using FTI-277 resulted in higher le vels of apoptosis after irradiation and increased radiosensitivity in H-ras-transformed rat embryo cells but did not affect control cells, T hese experiments suggest that farnesylation inhibitors may prove clini cally useful as radiosensitizers of tumors that depend on ras function .