title: Anticancer activity of oncolytic adenovirus vector armed with IFN-alpha and ADP is enhanced by pharmacologically controlled expression of TRAIL.
abstract: We have previously described oncolytic adenovirus (Ad) vectors KD3 and KD3-interferon (IFN) that were rendered cancer-specific by mutations in the E1A region of Ad; these mutations abolish binding of E1A proteins to p300/CBP and pRB. The antitumor activity of the vectors was enhanced by overexpression of the Adenovirus Death Protein (ADP, E3-11.6K) and by replication-linked expression of IFN-alpha. We hypothesized that the anticancer efficacy of the KD3-IFN vector could be further improved by expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). E1-deleted Ad vectors were constructed carrying reporter genes for enhanced green fluorescent protein or secreted placental alkaline phosphatase (SEAP) and a therapeutic gene for TRAIL under control of the TetON system. Expression of the genes was increased in the presence of a helper virus and the inducer doxycycline such that up to 231-fold activation of expression for the TetON-SEAP vector was obtained. Coinfection with TetON-TRAIL augmented oncolytic activity of KD3 and KD3-IFN in vitro. Induction of TRAIL expression did not reduce the yield of progeny virus. Combination of TetON-TRAIL and KD3-IFN produced superior antitumor activity in vivo as compared with either vector alone demonstrating the efficacy of a four-pronged cancer gene therapy approach, which includes Ad oncolysis, ADP overexpression, IFN-alpha-mediated immunotherapy, and pharmacologically controlled TRAIL activity.
authors.affiliation: VirRx Inc., St Louis, MO, USA.
authors.forename: E V
authors.initials: EV
authors.lastname: Shashkova
authors.forename: M N
authors.initials: MN
authors.lastname: Kuppuswamy
authors.forename: W S M
authors.initials: WS
authors.lastname: Wold
authors.forename: K
authors.initials: K
authors.lastname: Doronin
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017503:Adenovirus E3 Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology
chemical_list: D017503:Adenovirus E3 Proteins; D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C099609:adenovirus death protein, Adenovirus; D013752:Tetracycline; D004318:Doxycycline