Farnesyltransferase inhibitor effects on prostate tumor micro-environment and radiation survival.
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.
Shi
Yuquan
Y
Department of Radiation Oncology, University of Pennsylvania, 185 John Morgan Bldg., Philadelphia, PA 19104-6072, USA.
Wu
Junmin
J
Mick
Rosemarie
R
Cerniglia
George J
GJ
Cohen-Jonathan
Elizabeth
E
Rhim
Johng S
JS
Koch
Cameron J
CJ
Bernhard
Eric J
EJ
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
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