Treatment of human hepatocellular carcinoma by the oncolytic herpes simplex virus G47delta

Jiani Wang; Lihua Xu; Weigen Zeng; Pan Hu; Musheng Zeng; Samuel D Rabkin; Renbin Liu

doi:10.1186/s12935-014-0083-y

Treatment of human hepatocellular carcinoma by the oncolytic herpes simplex virus G47delta

Cancer Cell Int. 2014 Sep 19;14(1):83. doi: 10.1186/s12935-014-0083-y. eCollection 2014.

Authors

Jiani Wang¹, Lihua Xu², Weigen Zeng³, Pan Hu¹, Musheng Zeng⁴, Samuel D Rabkin⁵, Renbin Liu¹

Affiliations

¹ Breast Cancer Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, 510630 Guangzhou, China.
² Department of Oncology and Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
³ Breast Cancer Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, 510630 Guangzhou, China ; Department of Colorectal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, 100021 Beijing, China.
⁴ State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Centre, Guangzhou, China.
⁵ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, USA.

Abstract

Background: Oncolytic herpes simplex virus (HSV) can replicate in and kill cancer cells while sparing the adjacent normal tissue. Hepatocellular carcinoma (HCC) is amongst the most common and lethal cancers, especially in Third World countries. In this study, the cytotoxicity of a third-generation oncolytic HSV, G47Δ, was investigated in different human HCC cell lines and in an immortalized human hepatic cell line. Additionally, subcutaneous models of HCC were established to evaluate the in vivo anti-tumor efficacy of G47Δ.

Methods: The HepG2, HepB, SMMC-7721, BEL-7404, and BEL-7405 human HCC cell lines and the HL-7702 human hepatic immortalized cell lines were infected with G47Δ at different multiplicities of infection (MOIs). The viability of infected cells was determined, and the G47Δ replication was identified by X-gal staining for LacZ expression. Two subcutaneous (s.c.) HCC tumor models of HCC were also established in Balb/c nude mice, which were intratumorally(i.t.) treated with either G47Δ or mock virus. Tumor volume and mouse survival times were documented.

Results: More than 95% of the HepG2, Hep3B,and SMMC-7721 HCC cells were killed on by day 5 after infection with a MOI's of 0.01. For the HL-7702 human hepatic immortalized cells, 100% of the cells were killed on by day 5 after infection with a MOI's of 0.01. The BEL-7404 HCC cell line was less susceptible with about 70% cells were killed by day 5 after infection with a MOI's of 0.01. Whereas the BEL-7405 HCC cells were the least susceptible, with only 30% of the cells were killed. Both the SMMC-7721 and BEL-7404 cells form aggressive sc tumor models. G47Δ replicates in the tumors, such that most of the tumors regressed after the G47Δ-treatment, and treated tumor-bearing mice survived much longer than the control animals.

Conclusions: G47Δ effectively kills human HCC cells and an immortalized hepatic cell line at low MOI. Intra-tumor injection of G47Δ can induce a therapeutic effect and prolong the survival of treated mice bearing SMMC-7721 and BEL-7404 subcutaneously (s.c.) tumors. Thus, G47Δ may be useful as a novel therapeutic agent for HCC.

Keywords: Cytotoxicity; Hepatocellular carcinoma; Oncolytic herpes simplex virus; Subcutaneous model.