title: Potential utility of BimS as a novel apoptotic therapeutic molecule.
abstract: We have previously demonstrated a 1000-fold induction of gene expression exclusive to Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) cells using an adenoviral vector (ad5.oriP). This platform allows us to explore tumor-specific gene therapy with BimS (ad5.oriP.BimS), a potent proapoptotic Bcl-2 family member. Ad5.oriP.BimS (25 infectious units (ifu)/cell) reduced C666-1 viability in a time- and dose-dependent manner to 15% survival. The effect was enhanced with radiation (6 Gy). Three days after infection, the proportion of apoptotic cells increased from 3.5% (control) to 47.5% (25 ifu/cell). Confocal microscopy demonstrated Bim colocalization to the mitochondria within 18 h of ad5.oriP.BimS infection. Ad5.oriP.BimS induced a 2.8-, 2.1-, and 1.85-fold increase in caspase-3, -8, and -9 activities, respectively. When C666-1 cells were infected with ad5.oriP.BimS (20 ifu/cell), no tumors formed in 7/9 mice followed for 100 days. Six intratumoral injections of ad5.oriP.BimS (1.5 x 10(9) ifu/dose) in combination with radiation were sufficient to cause almost complete disappearance of established C666-1 or C15 xenograft tumors. Intravenous injections of ad5.oriP.BimS (10(9) ifu) induced mild perturbation in liver function tests, associated with hepatocyte apoptoses and mitoses. This vector appears to be safe and effectively cytotoxic to EBV-positive NPC cells both in vitro and in vivo, mediated primarily through the induction of apoptosis.
authors.affiliation: Division of Experimental Therapeutics, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2M9.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Yip
authors.forename: Anna
authors.initials: A
authors.lastname: Li
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Marie C
authors.initials: MC
authors.lastname: Chia
authors.forename: Shahnaz Al
authors.initials: SA
authors.lastname: Rashid
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Mocanu
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Louie
authors.forename: Otto
authors.initials: O
authors.lastname: Sanchez
authors.forename: Dolly
authors.initials: D
authors.lastname: Huang
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Ralph
authors.initials: R
authors.lastname: Gilbert
authors.forename: Brian
authors.initials: B
authors.lastname: O'sullivan
authors.forename: Patrick
authors.initials: P
authors.lastname: Gullane
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003131:Combined Modality Therapy; D004789:Enzyme Activation; D005720:Gamma Rays; D015316:Genetic Therapy / Q000009:adverse effects; D004854:Herpesvirus 4, Human; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D014183:Transplantation, Heterologous
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases