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World J Gastroenterol. Aug 7, 2007; 13(29): 4006-4010
Published online Aug 7, 2007. doi: 10.3748/wjg.v13.i29.4006
Vascular damage and anti-angiogenic effects of tumor vessel-targeted adenovirus-mediated herpes simplex virus thymidine kinase gene
Bao-Jin Li, Chao Zhang, Yuan-Xue Yi, Ying Hao, Xiao-Ping Liu, Qing-Jia Ou
Bao-Jin Li, Department of Hepatobiliary and Laparoscopic Surgery, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, Guangdong Provice, China
Chao Zhang, Yuan-Xue Yi, Ying Hao, Xiao-Ping Liu, Department of Hepatobiliary and Laparoscopic Surgery, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, Guangdong Province, China
Qing-Jia Ou, Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China
Author contributions: All authors contributed equally to the work.
Supported by the National Natural Science Foundation of China, No. 30371386, and the Natural Science Foundation of Guangdong Province, No. 31010
Correspondence to: Dr. Xiao-Ping Liu, Department of Hepatobillary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, No. 1120, Lianhua Road, Shenzhen 518036, Guangdong Province, China. ninliu@163.com
Telephone: +86-755-83923333-8707
Received: February 12, 2007
Revised: March 3, 2007
Accepted: April 7, 2007
Published online: August 7, 2007
Abstract

AIM: To explore the therapeutic efficacy and mechanism of herpes simplex virus-thymidine kinase (HSV-tk) targeting angiogenesis against hepatocellular carcinoma in vivio and in vitro.

METHODS: Recombinant adenovirus containing kinase domain insert with receptor (KDR) or cytomegalovirus (CMV) promoter-controlled HSV-tk gene (AdKDR-tk and AdCMV-tk) was constructed using pAdeasy system. The expression of KDR antigen in human umbilical venous endothelial cells (HUVEC) and HepG2 was detected with histological analysis of cells. The virus was used to infect HUVEC and HepG2. Following administration of ganciclovir (GCV), the survival rate of gene-transfected HUVEC and HepG2 was evaluated by MTT method. To develop hepatocarcinomas in 32 Balb/C mice with HepG2 cells, the mice were divided into four groups: ganciclovir group (I), Ad group (II), AdCMV-tk group (III) and AdKDR-tk group (IV). Then selective administration of recombinant adenovirus or Ad via the intratumorial was given to all rats. Ganciclovir (GCV) was given at a dose of 100 mg·kg-1·d-1 (ip) started on the following day and lasted 10 d. Microvessel density (MVD) of tumor in all the treated animals were examined by the immunohistochemical methods and tumor burden was evaluated 10 d before and after the last GCV dose.

RESULTS: Immunocytochemical staining indicated the expression of KDR antigen in HUVEC. Under adenovirus infection index of 100, with increasing GCV concentration from 0 up to 50 mg/L, the survival rate of AdKDR-tk-transfected HUVEC and HepG2 decreased from 100% to (28.94 ± 5.67)% and (75.45 ± 2.91)% at proper order, respectively (P < 0.01), while the survival rate of AdCMV-tk-transfected HUVEC and HepG2 declined from 100% to (17.56 ± 2.48)% and (23.15 ± 5.72)%, respectively (P > 0.05). Compared with groupI, there was a decrease of tumor weight by 14.7% in group III and by 23.6% in group IV. And there was a distinct difference between group III and IV (P < 0.05). The median MVD for all groups was 37.4 ± 8.6, 30.6 ± 7.8, 27.6 ± 7.1, and 10.7 ± 4.1 (microvessels/mm2) in groupI, II, III and IV, respectively. And there was a marked difference between group III and II (P < 0.05), IV and II (P < 0.01), and IV and III (P < 0.01).

CONCLUSION: KDR promoter-HSV-tk gene may effectually restrain the growth of tumor via targeting angiogenesis for hepatocellular carcinoma with treatment of GCV.

Keywords: Anti-angiogenic; Vessel-targeted; Adenovirus; Hepatocellular carcinoma; Herpes simplex virus thymidine kinase; Gene therapy