title: 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.affiliation: Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Nichollaq
authors.initials: N
authors.lastname: Vozhilla
authors.forename: Lejuan
authors.initials: L
authors.lastname: Chatman
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D039821:Monoterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D039821:Monoterpenes; D000099180:Interleukin-24; C032208:perillyl alcohol