Experimental Study of pcDNA3/AFP/TK/Angio Fusion Gene Targeting Therapy for Human Primary Liver Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

SHENG Qinsong , WANG Lin , REN Feng , LU Yonggang , ZOU Hao , XIAO Shufeng , TANG Bo , HUANG Jie , ZHANG Jie

Department of Hepatobiliary Surgery， The Second Affiliated Hospital of Kunming Medical College, Kunming 650101, China;

Corresponding author：

Keywords：

Primary liver cancer; Gene therapy; Target; Fusion gene; Angiostatin gene; Suicide gene

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Objective 　To study the effects of pcDNA3/AFP/TK/Angio fusion gene targeting therapy for human primary liver cancer in nude mice implanted with SMMC-7721.
Methods 　 Human liver cancer cell line SMMC-7721 was implanted subcutaneously in nude mice to establish experiment model. Animals bearing liver cancer were randomly divided into five groups: control group， vector group， GCV (ganciclovir) group， pcDNA3/TK/Angio group; pcDNA3/AFP/TK/Angio group. Different plasmids were directly injected into tumors and GCV was intraperitoneally administrated simultaneously according to different groups. The growth of tumors was observed and the pathology was examined as well. Serum AFP level was measured by radioimmunology, the ultrastructural change of tumor cells was studied by using electron microscopy, the expressions of MVD and VEGF were respectively detected with immunohistochemistry and the cell apoptosis in situ was detected by TUNEL.
Results 　The success rate to establish subcutaneous implanted liver cancer model in nude mice was 100%. The tumor volume, serum AFP level, VEGF and MVD expressions of pcDNA3/TK/Angio group and pcDNA3/AFP/TK/Angio group were lower than those in control group, vector group and GCV group (P＜0.05) and more apoptosis cells could be observed. While the tumor volume, serum AFP level, VEGF and MVD expressions of pcDNA3/AFP/TK/Angio group was lower than those in pcDNA3/TK/Angio group (P＜0.05); and apoptosis index was higher than that of the latter (P＜0.05).
Conclusion 　pcDNA3/AFP/TK/Angio fusion gene inhibits the growth of tumor remarkably and becomes a promising new biological agent to treat human primary liver cancer.

Citation： SHENG Qinsong,WANG Lin,REN Feng,LU Yonggang,ZOU Hao,XIAO Shufeng,TANG Bo,HUANG Jie,ZHANG Jie. Experimental Study of pcDNA3/AFP/TK/Angio Fusion Gene Targeting Therapy for Human Primary Liver Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2007, 14(4): 403-408. doi: Copy

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12.	李晓, 王琳, 郭永章, 等. 血管生成抑制素基因对裸鼠人肝癌移植瘤的治疗作用 [Ｊ]　. 中华实验外科杂志, 2004; 21(7)∶875　.
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1. 　Choi EA, Lei H, Maron DJ, et al. Combined 5-fluorouracil/systemic interferon-beta gene therapy results in long-term survival in mice with established colorectal liver metastases [Ｊ]　. Clin Cancer Res, 2004; 10(4)∶1535.
2. 　Hwang KS, Cho WK, Yoo J, et al. Adenovirus-mediated interleukin-12 gene transfer combined with cytosine deaminase followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice [Ｊ]　. BMC Cancer, 2005; 5(1)∶51.
3. 　You TG, Wang HS, Yang JH, et al. Transfection of IL-2 and/or IL-12 genes into spleen in treatment of rat liver cancer [Ｊ]　. World J Gastroenterol, 2004; 10(15)∶2190.
4. 　Chang CJ, Chen YH, Huang KW, et al. Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors [Ｊ]　. Hepatology, 2007; 45(3)∶746.
5. 　黄畦, 陈大瑜, 付向宁, 等. 双自杀基因重组腺病毒对肺癌细胞的杀伤作用 [Ｊ]　. 中华实验外科杂志, 2006; 23(4)∶579.
6. 　李梅生, 梁力建, 黄洁夫, 等. HSV-tk/CD融合基因杀伤人胆管癌细胞QBC939的体内实验 [Ｊ]　. 中国普外基础与临床杂志, 2005; 12（6）∶581.
7. 　Li PY, Lin JS, Feng ZH, et al. Combined gene therapy of endostatin and interleukin 12 with polyvinylpyrrolidone induces a potent antitumor effect on hepatoma [Ｊ]　. World J Gastroenterol, 2004; 10(15)∶2195.
8. 　Tai KF, Chen PJ, Chen DS, et al. Concurrent delivery of GM-CSF and endostatin genes by a single adenoviral vector provides a synergistic effect on the treatment of orthotopic liver tumors [Ｊ]　. J Gene Med, 2003; 5(5)∶386.
9. 　Shi M, Wang FS, Wu ZZ. Synergetic anticancer effect of combined quercetin and recombinant adenoviral vector expressing human wild-type p53, GM-CSF and B7-1 genes on hepatocellular carcinoma cells in vitro [Ｊ]　. World J Gastroenterol, 2003; 9(1)∶73.
10. 　Sung MW, Yeh HC, Thung SN, et al. Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase Ⅰ clinical trial [Ｊ]　. Mol Ther, 2001; 4(3)∶182.
11. 　Xu R, Sun X, Tse LY, et al. Long-term expression of angiostatin suppresses metastatic liver cancer in mice [Ｊ]　. Hepatology, 2003; 37(6)∶1451.
12. 　李晓, 王琳, 郭永章, 等. 血管生成抑制素基因对裸鼠人肝癌移植瘤的治疗作用 [Ｊ]　. 中华实验外科杂志, 2004; 21(7)∶875　.
13. 　Shi YJ, Gong JP, Liu CA, et al. Construction of a targeting adenoviral vector carrying AFP promoter for expressing EGFP gene in AFP-producing hepatocarcinoma cell [Ｊ]　. World J Gastroenterol, 2004; 10(2)∶186.
14. 　Huang X, Zhang W, Wakimoto H, et al. Adenovirus-mediated tissue-specific cytosine deaminase gene therapy for human hepatocellular carcinoma with different AFP expression levels [Ｊ]　. J Exp Ther Oncol, 2002; 2(2)∶100.
15. 　Ohguchi S, Nakatsukasa H, Higashi T, et al. Expression of alpha-fetoprotein and albumin genes in human hepatocellular carcinomas: limitations in the application of the genes for targeting human hepatocellular carcinoma in gene therapy [Ｊ]　. Hepatology, 1998; 27(2)∶599.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Experimental Study of pcDNA3/AFP/TK/Angio Fusion Gene Targeting Therapy for Human Primary Liver Cancer

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