title: Adenovirus-Mediated Expression of the p14 Fusion-Associated Small Transmembrane Protein Promotes Cancer Cell Fusion and Apoptosis In Vitro but Does Not Provide Therapeutic Efficacy in a Xenograft Mouse Model of Cancer.
abstract: Adenoviruses (Ads) are used in numerous preclinical and clinical studies for delivery of anti-cancer therapeutic genes. Unfortunately, Ad has a poor ability to distribute throughout a tumor mass after intratumoral injection, and infects cells primarily within the immediate area of the injection tract. Thus, Ad-encoded transgene expression is typically limited to only a small percentage of cells within the tumor. One method to increase the proportion of the tumor impacted by Ad is through expression of fusogenic proteins. Infection of a single cell with an Ad vector encoding a fusogenic protein should lead to syncytium formation with adjacent cells, effectively spreading the effect of Ad and Ad-encoded therapeutic transgenes to a greater percentage of the tumor mass. Moreover, syncytium formation can be cytotoxic, suggesting that such proteins may be effective sole therapeutics. We show that an early region 1 (E1)-deleted Ad expressing reptilian reovirus p14 fusion-associated small transmembrane (FAST) protein caused extensive cell fusion in the replication-permissive 293 cell line and at high multiplicity of infection in non-permissive human lung adenocarcinoma A549 cells in vitro. FAST protein expression in the A549 cancer cell line led to a loss of cellular metabolic activity and membrane integrity, which correlated with induction of apoptosis. However, in an A549 xenograft CD-1 nude mouse cancer model, Ad-mediated FAST gene delivery did not induce detectable cell fusion, reduce tumor burden nor enhance mouse survival compared to controls. Taken together, our results show that, although AdFAST can enhance cancer cell killing in vitro, it is not effective as a sole therapeutic in the A549 tumor model in vivo.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Poulin
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Tong
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Carin
authors.initials: C
authors.lastname: Christou
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kennedy
authors.affiliation: Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.|Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.|Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.|Centre for Neuromuscular Disease, University of Ottawa, ON, Ottawa, Canada.|Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Parks
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D002459:Cell Fusion; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D012087:Reoviridae / Q000235:genetics; D014760:Viral Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D014760:Viral Fusion Proteins; D017361:Viral Nonstructural Proteins