Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer Journal Article
| Authors: | Sepp-Lorenzino, L.; Tjaden, G.; Moasser, M. M.; Timaul, N.; Ma, Z.; Kohl, N. E.; Gibbs, J. B.; Oliff, A.; Rosen, N.; Scher, H. I. |
| Article Title: | Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer |
| Abstract: | The effects of farnesyl:protein transferase inhibitors (FTIs) were evaluated against hormone-dependent and hormone-independent prostate cancer cell lines harboring mutant and wild type Ras. The combinations of the FTI with hormones and chemotherapy were explored. The effect of FTI on the growth of human prostate cancer lines was examined under anchorage-dependent and -independent conditions. Changes in Ras processing and cellular localization were examined by immunoblotting and immunocytochemistry. Hormone-dependent (LNCaP) and -independent (TSU-Pr1, PC3 and DU145) human prostate cancer cell lines were growth-inhibited by the FTI L-744,832 at concentrations ranging from 100 nM to 20 μM. The inhibition was accompanied by loss of protein farnesylation and with the accumulation of Ha-Ras as its unprocessed, cytosolic form. No effect on N- and Ki-Ras processing was observed. The transformed phenotype of TSU-Pr1 cells, which possess a Ha-Ras Gly-12-Val activating mutation, reverted following FTI treatment. Enhanced antitumor effects were observed when the FTI was combined with gamma-radiation, etoposide, doxorubicin, cisplatin, estramustine and the antihormone bicalutamide. In particular, the combination of taxol and FTI was synergistic for DU145 cells, a cell 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 presence of mutations of tumor suppressors, cell cycle regulators and of the activation of a variety of oncogenes, including Ras. A cell line expressing mutated Ha-Ras is particularly sensitive. Enhanced antitumor effects were observed with an anti-androgen, γ-irradiation, and several chemotherapeutic agents. These findings support the clinical evaluation of FTIs alone or in combination as treatment for this disease. |
| Keywords: | cancer chemotherapy; controlled study; gene mutation; human cell; cisplatin; doxorubicin; cancer growth; paclitaxel; protein localization; phenotype; cell cycle; etoposide; antineoplastic activity; cancer cell culture; drug effect; drug screening; oncogene h ras; cancer hormone therapy; prostate cancer; cancer inhibition; oncogene; tumor suppressor gene; gene activation; protein processing; immunocytochemistry; cell transformation; 2 [[2 [[2 [(2 amino 3 mercaptopropyl)amino] 3 methylpentyl]oxy] 1 oxo 3 phenylpropyl]amino] 4 (methylsulfonyl)butanoic acid isopropyl ester; protein farnesyltransferase inhibitor; immunoblotting; cellular distribution; ras protein; antiandrogen; bicalutamide; concentration (parameters); drug sensitivity; anchorage independent growth; ras; cytosol; mutant; oncogene n ras; gamma radiation; estramustine; hormone dependence; prenylation; human; priority journal; article |
| Journal Title: | Prostate Cancer and Prostatic Diseases |
| Volume: | 4 |
| Issue: | 1 |
| ISSN: | 1365-7852 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2001-01-01 |
| Start Page: | 33 |
| End Page: | 43 |
| Language: | English |
| PROVIDER: | scopus |
| PUBMED: | 12497061 |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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