双靶向溶瘤腺病毒携带内皮抑素基因对肝癌的抑制作用  

Inhibitory effect of dual-regulated oncolytic adenovirus carrying mouse endostatin gene on hepato- cellular carcinoma xenografts in nude mice

作　　者：孙立臣[1] 潘旭波[1] 周先亭[1] 宋占文[1] 苏长青[2] 

机构地区：[1]青岛大学医学院附属炯台毓璜顶医院肝胆外科,264000 [2]第二军医大学东方肝胆外科医院分子肿瘤研究室

出　　处：《中华实验外科杂志》2012年第8期1529-1531,共3页Chinese Journal of Experimental Surgery

基　　金：烟台市科学技术发展计划资助项目（2005131.5）

摘　　要：目的构建双调控溶瘤腺病毒，携带小鼠内皮抑素基因（mE），研究其对裸鼠肝癌移植瘤的抗瘤活性。方法以人端粒酶逆转录酶启动子（hTERT）和缺氧调控元件序列（HRE）调控腺病毒Ela和Elb基因，基因组插入mE基因，构建双调控溶瘤腺病毒CNHK500-mE；在裸鼠模型中观察CNHK500．mE对肝癌移植瘤模型的疗效。结果CNHK500能够在hTERT阳性的肝癌细胞中增殖[24h：（16．67±4．04）％；48h：（65．33±7．02）％；P〈0．01]，并介导mE高效表达；与空白对照组（1895．80±323．37）mm3比较，CNHK500-mE和Ad—mE的抑瘤率分别为50．95％[（929．80±211．10）mm3，P〈0．01]和29．99％[1327．234-319．36）mm3,P〈0．05]；CNHK500-mE对癌组织问质血管的抑制作用明显强于Ad-mE（P〈0．05）。结论将mE与溶瘤腺病毒结合，发挥病毒增殖的溶瘤作用和基因产物的血管抑制作用，表现卅明显的协同抗瘤作用。Objective Dual-regulated oncolytic adenovirus carrying mouse endostatin gene （mE） was constructed, and its antitumor activity was examined in hepatoeellular carcinoma （HCC） xenografts in nude mice. Methods Human telomerase reverse transcriptase promoter （hTERT） and hypoxia regulatory element （HRE） were used to control adenoviral Ela and Elb genes. The mouse endostatin gene was in- serted into the viral genome to generate the dual-regulated oncolytic adenovirus CNHK500-mE. Its antitu- mor activity was observed in HCC models in nude mice. Results CNHK500 could replicate in hTERT-pos- itive HCC cells [24 h： （ 16. 67 ±4. 04） % ; 48 h： （65.33 ±7.02） % ;P 〈0. 01 ], and efficiently mediate endostatin expression; As compared with the control group （ 1895.80± 323.37） mm3 , CNHK500-mE and Ad-mE showed antitumor efficacy on the growth of HCC xenografts, with the tumor inhibition rate of 50.95% [ （ 929. 80 ±211.10 ） mm3,P〈0.01 and29.99% [（1327.23 ±319.36） mm3,p〈0.05], and the effect of CNHK500-mE was stronger than that of Ad-mE （P 〈0. 01 ）. Pathological examinations of xenograft tumors showed that CNHKS00-mE proliferated in cancer cells and expressed high levels of en- dostatin, and the inhibitory effect of CHNKSOO-mE on tumor microvessels was also stronger than that of Ad- mE （P 〈 0. 05 ）. Injection of CHNK500-mE resulted in large area of tumor necrosis. Conclusion Combi- nation of endostatin gene and dual-regulated oncolytic adenovirus exerts not only the oncolytic effect but also the tumor microvessel inhibition, finally produces the synergistic effect and enhances the antitumor efficacy.

关 键 词：癌 肝细胞 溶瘤腺病毒 内皮抑素基因 基因治疗 

分 类 号：R735[医药卫生—肿瘤]