title: Combination of oncolytic adenovirotherapy and Bax gene therapy in human cancer xenografted models. Potential merits and hurdles for combination therapy.
abstract: Cancer gene therapy and oncolytic virotherapy have been studied extensively. However, their clinical application is hampered by their weak anticancer activity. We previously constructed a replicating adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of the adenoviral E1 genes, and causes selective lysis of human cancer cells. We hypothesized that combination adenoviral therapy containing OBP-301 and a nonreplicating adenovirus expressing the proapoptotic Bax gene could overcome the weakness and augment the anticancer efficacy of each modality. Combination treatment resulted in marked Bax protein expression and enhanced efficacy in in vitro cell viability assay, when compared with either single treatment. However, combination treatment was not as effective in suppressing both subcutaneous and pleural disseminated tumors compared with OBP-301 treatment alone. Further investigation revealed that combination treatment resulted in suppressed E1A protein expression associated with reduced viral replication. Our results suggest that Bax gene therapy in combination with oncolytic adenovirotherapy potentially augments their antitumor activity, but further improvements may be required to maximize the combinatorial effect in vivo, for the Bax gene expression to avoid interference with production of the oncolytic virus.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Hioki
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.forename: Toshiya
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Ryo
authors.initials: R
authors.lastname: Sakai
authors.forename: Toru
authors.initials: T
authors.lastname: Kojima
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Yuuri
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Futoshi
authors.initials: F
authors.lastname: Uno
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods; D016133:Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: D051028:bcl-2-Associated X Protein