Farnesyl : protein transferase inhibitors as potential agents for the management of human prostate cancer

The effects of farnesyl:protein transferase inhibitors (FTIs) were evaluate d against hormone-dependent and hormone-independent prostate cancer cell li nes harboring mutant and wild type pas. The combinations of the FTI with ho rmones and chemotherapy were explored. The effect of FTI on the growth of h uman prostate cancer lines was examined under anchorage-dependent and -inde pendent conditions. Changes in Ras processing and cellular localization wer e examined by immunoblotting and immunocytochemistry. Hormone-dependent (LN CaP) and -independent (TSU-Pr1, PC3 and DU145) human prostate cancer cell l ines were growth-inhibited by the FTI L-744,832 at concentrations ranging f rom 100 nM to 20 muM. The inhibition was accompanied by loss of protein far nesylation and with the accumulation of Ha-Ras as its unprocessed, cytosoli c form. No effect on N- and Ki-Ras processing was observed. The transformed phenotype of TSU-Prl cells, which possess a Ha-Ras Gly-12-Val activating m utation, reverted following FTI treatment. Enhanced antitumor effects were observed when the FTI was combined with gamma-radiation, etoposide, doxorub icin, cisplatin, estramustine and the antihormone bicalutamide. In particul ar, the combination of taxol and FTI was synergistic for DU145 cells, a cel l line that is only marginally sensitive to the FTI alone. The sensitivity of human prostate cancer cell lines to the FTI is independent of the presen ce of mutations of tumor suppressors, cell cycle regulators and of the acti vation of a variety of oncogenes, including pas. A cell line expressing mut ated Ha-Ras is particularly sensitive. Enhanced antitumor effects were obse rved with an antiandrogen, gamma -irradiation, and several chemotherapeutic agents. These findings support the clinical evaluation of FTIs alone or in combination as treatment for this disease.