Adenoviral Oncolytic Suicide Gene Therapy for a Peritoneal Dissemination Model of Gastric Cancer in Mice

Yu Imamura MD, Shinji Ishikawa MD, PhD, Nobutaka Sato MD, Ryuichi Karashima MD, Kotaro Hirashima MD, Yukiharu Hiyoshi MD, Youhei Nagai MD, Yoshikatsu Koga MD, Naoko Hayashi MD, PhD, Masayuki Watanabe MD, PhD, Gen Yamada PhD, Hideo Baba MD, PhD, FACS
Translational Research and Biomarkers
Volume 17, Issue 2 / February , 2009

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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.

Conclusion

It was possible to reduce the total adenoviral dose of oncolytic suicide gene therapy while still preserving the antitumor effect.

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