title: Adenoviral oncolytic suicide gene therapy for a peritoneal dissemination model of gastric cancer in mice.
abstract: BACKGROUND
  Peritoneal dissemination of gastric cancer is often refractory to systemic therapies. Although adenoviral gene therapy has been reported to be a potentially useful therapeutic modality, the adenovirus itself has a dose-limiting toxicity. A novel system was constructed using adenoviral oncolytic suicide gene therapy targeting carcinoembryonic antigen (CEA), and its therapeutic effect and the possibility to reduce the total viral dose while still preserving the antitumor effect were assessed.
  
  
  METHODS
  Three types of adenoviruses were prepared for this novel system: (A) Ad/CEA-Cre, (B) Ad/lox-CD::UPRT for a Cre/loxP system, and (C) Ad/CEA-E1 for conditionally replicating adenovirus. The antitumor effect of the oncolytic suicide gene therapy (A + B + C) was then evaluated in vitro. Mice bearing peritoneal dissemination of human gastric cancer were treated with either this system (A + B + C) or with a tenfold viral dose of suicide gene therapy (A + B). The adverse effects in terms of hepatotoxicity were then evaluated between the two groups.
  
  
  RESULTS
  The current system (A + B + C) demonstrated significantly better cytotoxic effect for CEA-producing cell lines than did suicide gene therapy (A + B) at the same viral dose in vitro. The effect of oncolytic suicide gene therapy was almost equal to that of the tenfold viral dose of suicide gene therapy in vivo. The hepatotoxicity of the two treated groups was also found to be equivalent.
  
  
  CONCLUSIONS
  It was possible to reduce the total adenoviral dose of oncolytic suicide gene therapy while still preserving the antitumor effect.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto-City, Kumamoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Shinji
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Sato
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Karashima
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hirashima
authors.forename: Yukiharu
authors.initials: Y
authors.lastname: Hiyoshi
authors.forename: Youhei
authors.initials: Y
authors.lastname: Nagai
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.forename: Naoko
authors.initials: N
authors.lastname: Hayashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002272:Carcinoembryonic Antigen; C045073:Cre recombinase; D019426:Integrases