title: Farnesyltransferase inhibitor effects on prostate tumor micro-environment and radiation survival.
abstract: BACKGROUND
  Ras activation by mutation, overexpression, or receptor signaling can increase tumor cell survival after irradiation.
  
  
  METHODS
  We examined whether inhibiting Ras activity with farnesyltransferase inhibitors (FTI) altered the radiosensitivity and tumor micro-environment in prostate tumors.
  
  
  RESULTS
  Treatment with FTIs L-744,832 or FTI-277 reduced clonogenic survival of prostate tumor cells expressing oncogenic H-ras after irradiation. PI3-kinase/Akt and MAPK signaling pathways were downregulated by FTIs in these cells. FTI treatment reduced tumor hypoxia and also reduced MMP-9 expression in tumors with activated mutant H-ras. FTI treatment did not, however, increase apoptosis in irradiated intestine, demonstrating that acute radiation injury of this normal tissue was not enhanced by FTIs.
  
  
  CONCLUSIONS
  FTIs can enhance the killing of prostate tumors with activated H-Ras. Together with the absence of increased acute toxicity to normal bowel, these results imply that FTI treatment should be further studied as a possible adjuvant to radiotherapy in the treatment of abdominal cancers with activated Ras signaling.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania, 185 John Morgan Bldg., Philadelphia, PA 19104-6072, USA.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Shi
authors.forename: Junmin
authors.initials: J
authors.lastname: Wu
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.forename: George J
authors.initials: GJ
authors.lastname: Cerniglia
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cohen-Jonathan
authors.forename: Johng S
authors.initials: JS
authors.lastname: Rhim
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Koch
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bernhard
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D011905:Genes, ras / Q000187:drug effects*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; C096856:FTI 277; C096898:L 744832; D011518:Proto-Oncogene Proteins; D011838:Radiation-Sensitizing Agents; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9