Acta Pharmacologica Sinica (2009) 30: 617?27; doi: 10.1038/aps.2009.33

Acta Pharmacologica Sinica (2009) 30: 617-627; doi: 10.1038/aps.2009.33; published online 13th April 2009

Original Article

Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models

Fei-qun ZHENG^1,#, Yin XU^2,3,#, Ren-jie YANG^1,*, Bin WU^{3, *}, Xiao-hua TAN⁴, Yi-de QIN², Qun-wei ZHANG³

¹Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Interventional Therapy, Peking University School of Oncology, Peking Cancer Hospital and Institute, Beijing 100142, China; ²Department of Biochemistry and Molecular Biology, Basic Medical Science School, Anhui Medical University, Hefei 230032, China; ³Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, China; ⁴Department of Hematology, Beijing Military General Hospital, Beijing 100700, China

Aim: Oncolytic adenovirus, also called conditionally replicating adenovirus (CRAD), can selectively propagate in tumor cells and cause cell lysis. The released viral progeny can infect neighboring cancer cells, initiating a cascade that can lead to the ultimate destruction of the tumor. Suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) offers a potential treatment strategy for cancer and is undergoing preclinical trials for a variety of tumors. We hypothesized that HSV-TK gene therapy combined with oncolytic adenoviral therapy would have an enhanced effect compared with the individual effects of the therapies and is a potential novel therapeutic strategy to treat liver cancer.

Methods: To address our hypothesis, a novel CRAD was created, which consisted of a telomerase-dependent oncolytic adenovirus engineered to express E 1A and HSV-TK genes (Ad-ETK). The combined effect of Ad-ETK and GCV was assessed both in vitro and in vivo in nude mice bearing HepG2 cell-derived tumors. Expression of the therapeutic genes by the transduced tumor cells was analyzed by RT-PCR and Western blotting.

Results: We confirmed that Ad-ETK had antitumorigenic effects on human hepatocellular carcinoma (HCC) both in vitro and in vivo, and the TK/GCV system enhanced oncolytic adenoviral therapy. We confirmed that both E 1A and HSV-TK genes were expressed in vivo.

Conclusion: The Ad-ETK construct should provide a relatively safe and selective approach to killing cancer cells and should be investigated as an adjuvant therapy for hepatocellular carcinoma.

Keywords: conditionally replicative adenovirus; cancer gene therapy; hepatocellular carcinoma; herpes simplex virus thymidine kinase; suicide gene therapy

We thank Prof Jun HAN (National Institute for Viral Disease Control and Preventions, Chinese Center for Disease Control and Prevention) and Zhao-zhang LU, Dong-dong ZHANG for helpful discussions and suggestions.

^#Fei-qun ZHENG and Yin XU contributed equally to this work.
* Correspondence to Prof Ren-jie YANG and Bin WU.
Emal renjieyang2007@163.com (Ren-jie YANG); wubin63@yahoo.com.cn (Bin WU).
Received 2008-11-16 Accepted 2009-03-05

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