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 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.
Bernhard
E J
EJ
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, 19104, USA.
Kao
G
G
Cox
A D
AD
Sebti
S M
SM
Hamilton
A D
AD
Muschel
R J
RJ
McKenna
W G
WG
D019883:Alkyl and Aryl Transferases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005347:Fibroblasts; D016259:Genes, myc; D011905:Genes, ras / Q000187:drug effects; D007700:Kinetics; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats; D014162:Transfection; D014166:Transferases / Q000037:antagonists & inhibitors*; D001749:Urinary Bladder Neoplasms / Q000235:genetics
D004791:Enzyme Inhibitors; C096856:FTI 277; D011838:Radiation-Sensitizing Agents; D008715:Methionine; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase