Adenoviral oncolytic suicide gene therapy for a peritoneal dissemination model of gastric cancer in mice.
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.
Imamura
Yu
Y
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto-City, Kumamoto, Japan.
Ishikawa
Shinji
S
Sato
Nobutaka
N
Karashima
Ryuichi
R
Hirashima
Kotaro
K
Hiyoshi
Yukiharu
Y
Nagai
Youhei
Y
Koga
Yoshikatsu
Y
Hayashi
Naoko
N
Watanabe
Masayuki
M
Yamada
Gen
G
Baba
Hideo
H
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
D002272:Carcinoembryonic Antigen; C045073:Cre recombinase; D019426:Integrases