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

Abstract

Objective Dual-regulated oncolytic adenovirus carrying mouse endostatin gene (mE) was constructed,and its antitumor activity was examined in hepatocellular 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 E1b genes.The mouse endostatin gene was inserted into the viral genome to generate the dual-regulated oncolytic adenovirus CNHKS00-mE.Its antitumor activity was observed in HCC models in nude mice.Results CNHK500 could replicate in hTERT-positive 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] and 29.99％ [(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 xenografi tumors showed that CNHK500-mE proliferated in cancer cells and expressed high levels of endostatin,and the inhibitory effect of CHNK500-mE on tumor microvessels was also stronger than that of AdmE ( P ＜ 0.05 ).Injection of CHNK500-mE resulted in large area of tumor necrosis.Conclusion Combination 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. Key words: Carcinoma,hepatocellular; Oncolytic adenovirus; Endostatin gene; Gene therapy