This study was carried out to test the hypothesis that RAS activation could contribute to prostate tumor radiation resistance and that farnesyltransferase inhibitor treatment of prostate tumor cells expressing activated ras oncogenes would reduce their clonogenic survival after irradiation. The studies undertaken have shown increased radiation survival in many, but not all prostate tumor cell lines expressing activated RAS proteins. Treatment of these cell lines and tumors derived from a subset of these cell lines with farnesyltransferase inhibitors resulted in decreased radiation survival both in vitro assays and when these cells were used to generate tumors in athymic nude mice. It was further shown that tumor oxygenation was enhanced after farnesyltransferase inhibitor treatment. Radiosensitization by farnesyltransferase inhibitors appears limited to those cells with activated ras. Further study will be needed to determine whether farnesyltransferase inhibitors can affect the radiosensitivity of prostate tumors expressing wild-type ras in vivo. Taken together these results demonstrate the potential of farnesyltransferase inhibitors in the treatment of certain prostate tumors.
Final rept. 1 Oct 1998-31 Mar 2001
--Original contains color plates: All DTIC reproductions will be in black and white.