Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis.
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.
Lebedeva
Irina V
IV
Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Su
Zhao-Zhong
ZZ
Vozhilla
Nichollaq
N
Chatman
Lejuan
L
Sarkar
Devanand
D
Dent
Paul
P
Athar
Mohammad
M
Fisher
Paul B
PB
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
D007378:Interleukins; D039821:Monoterpenes; D000099180:Interleukin-24; C032208:perillyl alcohol