Journal Article

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

Ren-jie Yang, Yi-de Qin, Yin Xu, Fei-qun Zheng, Qun-wei Zhang, Bin Wu, Xiao-hua Tan

2009

Overview

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.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group
• Subject: Adenoviridae / Adenoviridae - genetics / Adenovirus / Animals / Biomedical and Life Sciences / Biomedicine / Carcinoma, Hepatocellular / Carcinoma, Hepatocellular - therapy / Cell Line, Tumor / Combined Modality Therapy / Ganciclovir / Ganciclovir - administration & dosage / Genes, Transgenic, Suicide / Genetic Therapy / Genetic Therapy - methods / Herpes simplex virus / Humans / Immunology / Internal Medicine / Liver Neoplasms, Experimental / Liver Neoplasms, Experimental - therapy / Medical Microbiology / Mice / Mice, Nude / Neoplasm Transplantation / Oncolytic Virotherapy / Oncolytic Virotherapy - methods / Original / original-article / Pharmacology/Toxicology / Simplexvirus / Simplexvirus - genetics / Thymidine Kinase / Thymidine Kinase - genetics / Vaccine