目的: 探讨重组腺病毒介导胸苷激酶系统通过血管靶向治疗裸鼠皮下人肝癌细胞移植瘤的疗效及作用机制。方法： 32只BALB/c鼠皮下接种建立裸鼠皮下人肝癌细胞移植瘤模型，当瘤体达100 mm3时随机分成4组，分别为更昔洛韦(GCV)组(Ⅰ)、空载体病毒组(Ⅱ)、重组腺病毒CMV-TK组(Ⅲ)及重组腺病毒AdKDR-TK组(Ⅳ)。各治疗组瘤内分别注入重组腺病毒液及空载体病毒液，重组腺病毒治疗组在病毒给予24 h后分别在腹腔内注射GCV，连续10 d；对照组腹腔内注入GCV。观察各组瘤体生长情况及免疫组化法测定肿瘤微血管密度(MVD)。结果： 与对照组比较，第Ⅲ、 Ⅳ组经治疗后肿瘤的生长均受到了明显的抑制，其抑瘤率分别为12.3%和24.5%（两者比较，P<0.05）。肿瘤组织内的MVD，Ⅰ组为（37.4±86）个/mm2、Ⅱ组为(30.6±7.8)个/mm2、Ⅲ组为(27.6±7.1)个/mm2、Ⅳ组为(10.7±4.1)个/mm2，其中Ⅲ组与Ⅱ组(P <005)、Ⅳ组与Ⅱ组(P<0.01)、Ⅳ组与Ⅲ组(P<0.01)之间的肿瘤内MVD比较均有统计学差异。结论： 重组腺病毒介导以KDR为启动子的胸苷激酶系统能够通过血管靶向性地有效抑制肿瘤的生长。

Objective: To explore the therapeutic efficacy and mechanism of herpes simplex virus thymidine kinase (HSV-TK) in blood vessel-targeted treatment of human hepatocellular carcinoma subcutaneously implanted in mice. Methods: Thirty-two BALB/C mice were subcutaneously transplanted with human hepatocellular carcinoma and the tumors were allowed to grow till the volume reached 100 mm3, then the mice were divided into 4 groups: Ganciclovir group （Ⅰ）, Ad group （Ⅱ）, AdCMV-TK+group GCV (Ⅲ) and AdKDR-TK + GCV group (Ⅳ). Recombinant adenovirus or Ad were injected intra-tumorally in all mice. Ganciclovir (GCV) was given at a dose of 100 mg/(kg·d) (ip) on the following day of injection for 10 days. Microvessel density (MVD) of the tumors was determined with the immunohistochemical methods and the growth of the tumors was observed. Results: Compared with groupⅠ, 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 MVD in group Ⅰ, Ⅱ, Ⅲ and Ⅳ was 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). Conclusion: Our results suggest that AdKDR-TK may effectively restrain the growth of hepatocellular carcinoma through inhibiting angiogenesis.

国家自然科学基金资助项目（30371386）； 广东省自然科学基金资助项目（31010）； 深圳市科技计划项目（200204093）