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Prostate. 2005 Jan 1;62(1):69-82.

Farnesyltransferase inhibitor effects on prostate tumor micro-environment and radiation survival.

Author information

1
Department of Radiation Oncology, University of Pennsylvania, 185 John Morgan Bldg., Philadelphia, PA 19104-6072, USA.

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.

PMID:
15389805
DOI:
10.1002/pros.20122
[Indexed for MEDLINE]

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