Chinese Journal of Cancer Research

, Volume 19, Issue 1, pp 22–26

Adenovirus-mediated herpes simplex virus thymidine kinase gene transfer driver by KDR promoter in treatment of experimental human hepatocelLular carcinoma in nude mice

  • Li Bao-jin  (李宝金)
  • Zhang Chao  (张超)
  • Yi Yuan-xue  (伊远学)
  • Hao Ying  (郝颖)
  • Liu Xiao-ping  (刘晓平)
  • Ou Qing-jia  (区庆嘉)



To investigate the therapeutic efficacy of adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) gene transfer under the driving of KDR promoter (AdKDR-tk) in combination of ganciclovir (GCV) against human hepatocellular carcinoma in nude mice.


HepG2 cell line was implanted subcutaneously into 32 nude mice, which were subsequently divided into 4 groups (n=8 each group): Ganciclovir group (I), Ad group (II), AdCMV-tk/GCV group (under the driving of CMV promoter) (III) and AdKDR-tk/GCV group (IV). Then intratumoral injection of recombinant adenovirus or Ad was performed in all nude mice, and repeated 24 h later. For the following 10 d GCV was given at a dose of 100 mg/(kg·d), ip. All the treated animals were killed to evaluate the tumor weight and the histopathological changes and the microvessel density of tumors after the treatment was determined.


Compared with group I, the tumor inhibitory rate was 12.3% in group III and 24.5% in group IV; the inhibition rates were significantly different between group III and IV (P<0.05). The mean MVDs in group I, II, III and IV were 37.4±8.6, 30.6±7.8, 27.6±7.1, and 10.7±4.1 (microvessels/mm2), respectively. Significant differences were found between group III and II (P<0.05), IV and II (P<0.01), and IV and III (P<0.01).


Intratumoral injection of AdKDR-tk results in marked inhibition of HCC growth through inhibition angiogenesis in nude mice. It may be a new treatment approach for human HCC.

Key words

Hepatocellular carcinoma KDR promoter Simpler virus Thymidine Kinase Adenovirus vector 

CLC number



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  1. [1]
    Di Bisceglie AM. Epidemiology and clinical presentation of hepatocellular carcinoma [J]. J Vasc Interv Radiol 2002; 13:S169–71.PubMedGoogle Scholar
  2. [2]
    Miao J, Chen GG, Chun SY, et al. Adenovirus-mediated tBid overexpression results in therapeutic effects on p53-resistant hepatocellular carcinoma [J]. Int J Cancer 2006; 119:1985:93.Google Scholar
  3. [3]
    Yang WY, Huang ZH, Lin LJ, et al. Kinase domain insert containing receptor promoter controlled suicide gene system selectively kills human umbilical vein endothelial cells [J]. World J Gastroenterol 2006;12:5331–5.PubMedGoogle Scholar
  4. [4]
    Shirakawa T, Gotoh A, Wada Y, et al. Tissue-specific promoters in gene therapy for the treatment of prostate cancer [J]. Mol Urol 2000; 4:73:82.Google Scholar
  5. [5]
    Saharinen P, Alotalo K. Double target for tumor mass destruction [J]. J Clin Invest 2003; 1114:1277–80.CrossRefGoogle Scholar
  6. [6]
    Sassa Y, Hata Y, Aiello LP, et al. Bifunctional Properties of peroxisome proliferator-activated receptor gammal in KDR gene regulation mediated via interaction with both Sp1 and Sp3 [J]. Diabetes 2004; 53:1222–9.PubMedCrossRefGoogle Scholar
  7. [7]
    Szary J, Kalita K, Przybyszewska M, et al. KDR promoter can transcriptionally target cytosine deaminase suicide gene to cancer cells of nonendothelial origin [J]. Anticancer Res 2001; 21:3471–5.PubMedGoogle Scholar
  8. [8]
    Shen BQ, Lee DY, Gerber HP, et al. Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth factor in vitrol [J]. J Biol Chem 1998; 273:29979–85.PubMedCrossRefGoogle Scholar
  9. [9]
    Ido A, Uto H, Moriuchi A, et al. Gene therapy targeting for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by a hypoxia-inducible enhancer linked to a human alpha-fetoprotein promoter [J]. Cancer Res 2001; 61:3016–21.PubMedGoogle Scholar
  10. [10]
    Poon RT, Zq IO, Lau C, et al. Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: a prospective study [J]. J Clin Oncol 2002; 20:1775–85.PubMedCrossRefGoogle Scholar
  11. [11]
    Zhang ZL, Liu ZS, Sun Q. Anti-tumor effect fo thalidomide and paclitaxel on hepatocellular carcinoma in nude mice [J]. Chin Med J 2005;118:1688–94.PubMedGoogle Scholar
  12. [12]
    Dutour A, Monteil J, Paraf F, et al. Endostatin cDNA/cationic liposome complexes as a promising therapy to prevent lung metastases in osteosarcoma: study in a human-like rat orthotopic tumor [J]. Mol Ther 2005; 11:311–9.PubMedCrossRefGoogle Scholar
  13. [13]
    Tandle A, Blazer DG 3rd, Libutti SK. Antiangiogenic gene therapy of cancerL recent developments [J]. J Transl Med 2004; 2:22.PubMedCrossRefGoogle Scholar
  14. [14]
    Ahlskog J, Paganelli G, Neri D. Vascular tumor targeting [J]. Q J Nucl Med Mol Imaging 2006; 50:296–309.PubMedGoogle Scholar
  15. [15]
    Wachsberger PR, Burd R, Marero N, et al. Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma [J]. Clin Cancer Res 2005; 11:835–42.PubMedGoogle Scholar
  16. [16]
    Poon RT, Lau CP, Cheung ST, et al. Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma [J]. Cancer Res 2003; 63:3121–6.PubMedGoogle Scholar
  17. [17]
    Ribatti D, Vacca A, Nico B, et al. Angiogenesis and anti-angiogenesis in hepatocellular carcinoma [J]. Cancer Treat Rev 2006; 32:437–44.PubMedCrossRefGoogle Scholar
  18. [18]
    Patterson C, Wu Y, Lee ME, et al. Nuclear protein interactions with the human KDR/flk-1 promoter in vivo. Regulation of Spl binding is associated with cell type-specific expression [J]. J Biol Chem 1997; 272:8410–6.PubMedCrossRefGoogle Scholar
  19. [19]
    Pastorino F, Brignole C, Marimpietri D, et al. Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy [J]. Cancer Res 2003; 63:7400–9.PubMedGoogle Scholar
  20. [20]
    Szary J, Kalita K, Przybyszewska M, et al. KDR promoter can transcriptionally target cytosine deaminase suicide gene to cancer cells of nonendothelial origin [J]. Anticancer Res 2001; 21:3471–5.PubMedGoogle Scholar
  21. [21]
    Jaggar RT, Chan HY, Harris AL, et al. Endothelial cell-specific expression of tumor necrosis factor-alpha from the KDR or E-selectin promoters following retroviral delivery [J]. Hum Gene Ther 1997; 8:2239–47.PubMedGoogle Scholar
  22. [22]
    Mavria G, Harrington KJ, Marshall CJ, et al. In vivo efficacy of HSV-TK transcriptionally targeted to the tumour vasculature is augmented by combination with cytotoxic chemotherapy [J]. J Gene Med 2005; 7:263–75.PubMedCrossRefGoogle Scholar
  23. [23]
    Tan R, Li C, Ma L. A novel and simple method for construction of recombinant adenoviruses [J]. Nucleic Acids Res 2006; 34:e89.PubMedCrossRefGoogle Scholar
  24. [24]
    Mullan B, Dugue C, Moutard V, et al. Robust functional gene validation by adenoviral vectors: one-step Escherichia coli-derived recombinant adenoviral genome construction [J]. Gene Ther 2004; 11:1599–1605.PubMedCrossRefGoogle Scholar
  25. [25]
    Liu XP, Li BJ, Zhang C. Construction and identification of recombinant vectors carrying herpes simplex virus thymidine kinase genes expressed in vascular endothelial cells [J]. Ai Zheng (Chin) 2006; 25:179–84.Google Scholar

Copyright information

© Chinese Anti-Cancer Association 2007

Authors and Affiliations

  • Li Bao-jin  (李宝金)
    • 1
    • 2
  • Zhang Chao  (张超)
    • 1
  • Yi Yuan-xue  (伊远学)
    • 1
  • Hao Ying  (郝颖)
    • 1
  • Liu Xiao-ping  (刘晓平)
    • 1
  • Ou Qing-jia  (区庆嘉)
    • 2
  1. 1.Department of Hepatobiliary and Laparoscopic Surgery, Peking University Shenzhen HospitalPeking University & Hongkong University of Science and Technology Shenzhen Medical CenterShenzhenChina
  2. 2.Department of Hepatobiliary Surgery, the Second Affiliated HospitalSun Yat-sen UniversityGuangzhouChina

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