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Research Articles: Therapeutics, Targets, and Development

Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis

Departments of ¹ Urology and ² Dermatology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York; and Departments of ³ Human and Molecular Genetics and ⁴ Biochemistry and Molecular Biology, ⁵ VCU Institute of Molecular Medicine, and ⁶ Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia

Requests for reprints: Paul B. Fisher, Department of Human and Molecular Genetics, Massey Cancer Center, Virginia Commonwealth University, School of Medicine, 1101 East Marshall Street, Sanger Hall Building, Room 11-015, Richmond, VA 23298-0033. Phone: 804-828-9632; Fax: 804-827-1124. E-mail: pbfisher{at}vcu.edu

Abstract

Pancreatic cancer is one of the deadliest of cancers. Even with aggressive therapy, the 5-year survival rate is <5%, mandating development of more effective treatments. Melanoma differentiation–associated gene-7/interleukin-24 (mda-7/IL-24) shows potent antitumor activity against most cancers displaying safety with significant clinical efficacy. However, pancreatic cancer cells display inherent resistance to mda-7/IL-24 that is the result of a "protein translational block" of mda-7/IL-24 mRNA in these tumor cells. We now show that a dietary supplement perillyl alcohol (POH) has significant chemopreventive effects for pancreatic cancer and, when coupled with adenovirus-mediated mda-7/IL-24 gene therapy (Ad.mda-7), effectively eliminates s.c. and i.p. xenografts of human pancreatic cancer cells in nude mice, promoting enhanced survival. The combination of POH and Ad.mda-7 efficiently abrogates the mda-7/IL-24 protein translational block, resulting in MDA-7/IL-24 protein production and growth suppression. Of direct translational relevance, clinically achievable concentrations of POH with Ad.mda-7, both of which have been found safe and without toxic effects in human trials, were used. This novel and innovative approach combining a dietary agent and a virally delivered therapeutic cytokine provides a means of both preventing and treating human pancreatic cancer with significant clinical translational potential. [Mol Cancer Ther 2008;7(7):2042–50]

Grant support: NIH grant R01 CA098712 and the Samuel Waxman Cancer Research Foundation. D. Sarkar is the Harrison Endowed Scholar in Cancer Research. P. Dent is the Universal Inc. Professor in Signal Transduction Research. P.B. Fisher holds the Thelma Newmeyer Corman Chair in Cancer Research and is a Samuel Waxman Cancer Research Foundation Investigator.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/17/08; revised 5/13/08; accepted 5/15/08.

This article has been cited by other articles:

				I. V. Lebedeva, Z.-z. Su, N. Vozhilla, L. Chatman, D. Sarkar, P. Dent, M. Athar, and P. B. Fisher Mechanism of In vitro Pancreatic Cancer Cell Growth Inhibition by Melanoma Differentiation-Associated Gene-7/Interleukin-24 and Perillyl Alcohol Cancer Res., September 15, 2008; 68(18): 7439 - 7447. [Abstract] [Full Text] [PDF]