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Farnesyltransferase inhibitor effects on prostate tumor micro‐environment and radiation survival
Author(s) -
Shi Yuquan,
Wu Junmin,
Mick Rosemarie,
Cerniglia George J.,
CohenJonathan Elizabeth,
Rhim Johng S.,
Koch Cameron J.,
Bernhard Eric J.
Publication year - 2005
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20122
Subject(s) - cancer research , prostate , farnesyltransferase inhibitor , farnesyltransferase , radiosensitivity , protein kinase b , medicine , clonogenic assay , radiation therapy , mapk/erk pathway , signal transduction , apoptosis , biology , cancer , prenylation , biochemistry , enzyme
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. © 2004 Wiley‐Liss, Inc.