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

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.

• Authors: Irina V Lebedeva, Zhao-Zhong Su, Nichollaq Vozhilla, Lejuan Chatman, Devanand Sarkar, Paul Dent, Mohammad Athar, Paul B Fisher
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 7 Pg. 2042-50 (Jul 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18645014 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukins
• Monoterpenes
• interleukin-24
• perillyl alcohol

Topics

• Adenoviridae (metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemoprevention
• Combined Modality Therapy
• Disease Models, Animal
• Genetic Therapy
• Humans
• Interleukins (genetics, therapeutic use)
• Mice
• Mice, Nude
• Monoterpenes (pharmacology, therapeutic use)
• Neovascularization, Pathologic
• Pancreatic Neoplasms (blood supply, genetics, pathology, prevention & control)
• Survival Analysis
• Xenograft Model Antitumor Assays