Vol43 No.10: 813-821

Cancer targeting Gene-Viro-Therapy specific for liver cancer by ��-fetoproteincontrolled oncolytic adenovirus expression of SOCS3 and IL-24

Xin Cao^1†, Ruicheng Wei^1,2,3†, Xinran Liu¹, Yan Zeng⁴, Hongling Huang¹, Miao Ding¹, Kangjian Zhang¹, and Xin-Yuan Liu^1,2*

(1 Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 2 Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou 310018, China; 3 Laboratory of Immune Regulation, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China 4Laboratory of Molecular Virology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China)

Abstract
����The combination of gene therapy and virotherapy for cancer treatment has received close attention and has become a trend in the field of cancer biotherapy. A strategy called ��Cancer Targeting Gene-Viro-Therapy�� (CTGVT) or ��Gene Armed Oncolytic Viral Therapy�� (GAOVT) has been proposed, in which an antitumor gene is inserted into an oncolytic viral vector. In our previous study, a dual-regulated oncolytic adenovirus with enhanced safety for normal cells and strict liver cancer-targeting ability, designated Ad•enAFP•E1A•E1B (��55) (briefly Ad•enAFP•D55), was successfully constructed. In the current work, interleukin-24 (IL-24) and suppressor of cytokine signaling 3 (SOCS3) genes were packaged into Ad•enAFP•D55. The new constructs, Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3), showed improved tumoricidal activity in hepatoma cell lines compared with the oncolytic viral vector Ad•enAFP•D55. The co-administration of Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3) showed much better antitumor effect than Ad•enAFP•D55-(IL-24) or Ad•enAFP•D55-(SOCS3) alone both in vitro and in a nude mouse xenograft model. Moreover, our results also showed that blockade of the Jak/Stat3 pathway by Ad•enAFP•D55-(SOCS3) infection in HuH-7 cells could down-regulate some anti-apoptosis proteins, such as XIAP, Bcl-xL, and survivin, which might sensitize the cells to Ad•enAFP•D55-(IL-24)-induced apoptosis. These results indicate that co-administration of Ad•enAFP•D55-(IL-24) and Ad•enAFP•D55-(SOCS3) may serve as a candidate therapeutic approach for the treatment of liver cancer.

Received: 2011-5-31����Accepted: 2011-6-19

†These authors contributed equally to this work.

*Corresponding author . Tel/Fax: +86-21-54921126; E-mail: [email protected]

Browse:94