Chemoprevention gene therapy (CGT) of pancreatic cancer using perillyl alcohol and a novel chimeric serotype cancer terminator virus.

Abstract

Conditionally replication competent adenoviruses (Ads) that selectively replicate in cancer cells and simultaneously express a therapeutic cytokine, such as melanoma differentiation associated gene- 7/Interleukin-24 (mda-7/IL-24), a Cancer Terminator Virus (CTV-M7), hold potential for treating human cancers. To enhance the efficacy of the CTV-M7, we generated a chimeric Ad.5 and Ad.3 modified fiber bipartite CTV (Ad.5/3-CTV-M7) that can infect tumor cells in a Coxsackie Adenovirus receptor (CAR) independent manner, while retaining high infectivity in cancer cells containing high CAR. Although mda-7/IL-24 displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells display an intrinsic resistance to mda-7/IL-24-mediated killing due to an mda-7/IL-24 mRNA translational block. However, using a chemoprevention gene therapy (CGT) approach with perillyl alcohol (POH) and a replication incompetent Ad to deliver mda-7/IL-24 (Ad.mda-7) there is enhanced conversion of mda-7/IL-24 mRNA into protein resulting in pancreatic cancer cell death in vitro and in vivo in nude mice containing human PDAC xenografts. This combination synergistically induces mda-7/IL-24-mediated cancer-specific apoptosis by inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum (ER) stress response through induction of BiP/GRP-78, which is most evident in chimeric-modified non-replicating Ad.5/3- mda-7- and CTV-M7-infected PDAC cells. Moreover, Ad.5/3-CTV-M7 in combination with POH sensitizes therapy-resistant MIA PaCa-2 cell lines over-expressing either Bcl-2 or Bcl-xL to mda-7/IL-24-mediated apoptosis. Ad.5/3-CTV-M7 plus POH also exerts a significant antitumor 'bystander' effect in vivo suppressing both primary and distant site tumor growth, confirming therapeutic utility of Ad.5/3-CTV-M7 plus POH in PDAC treatment, where all other current treatment strategies in clinical settings show minimal efficacy.

• Authors: S Sarkar, B Azab, B A Quinn, X Shen, P Dent, A L Klibanov, L Emdad, S K Das, D Sarkar, P B Fisher
• Journal: Current molecular medicine (Curr Mol Med) Vol. 14 Issue 1 Pg. 125-40 (Jan 2014) ISSN: 1875-5666 [Electronic] Netherlands
• PMID: 24236457 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Interleukins
• Monoterpenes
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• bcl-X Protein
• interleukin-24
• perillyl alcohol

Topics

• Adenoviridae (genetics)
• Animals
• Antineoplastic Agents (administration & dosage)
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Chemoprevention
• Disease Models, Animal
• Endoplasmic Reticulum Stress
• Gene Expression
• Genetic Therapy
• Genetic Vectors (administration & dosage, genetics)
• Humans
• Interleukins (genetics)
• Mice
• Monoterpenes (administration & dosage)
• Organ Specificity (genetics)
• Pancreatic Neoplasms (genetics, pathology, therapy)
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays
• bcl-X Protein (genetics)