Original Article
Acta Pharmacologica Sinica (2009) 30: 617–627; doi: 10.1038/aps.2009.33; published online 13th April 2009
Combination effect of oncolytic adenovirus therapy and herpes simplex virus thymidine kinase/ganciclovir in hepatic carcinoma animal models
Fei-qun Zheng1,#, Yin Xu2,3,#, Ren-jie Yang1, Bin Wu3, Xiao-hua Tan4, Yi-de Qin2 and 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
Correspondence: Prof Ren-jie Yang, E-mail renjieyang2007@163.com; Prof Bin Wu, E-mail wubin63@yahoo.com.cn
#Fei-qun Zheng and Yin Xu contributed equally to this work.
Received 16 November 2008; Accepted 5 March 2009; Published online 13 April 2009.
Abstract
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 E1A 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 E1A 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
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