人甲胎蛋白启动子控制HIV-1Vpr表达的重组腺病毒体内抑瘤效果研究

Tumor-suppressing effect of recombinant adenovirus encoding HIV-1 Vpr gene driven by human alpha-fetoprotein promoter in nude mice

目的:研究人甲胎蛋白启动子控制表达HIVVpr基因的重组腺病毒对裸鼠肝癌模型的肿瘤组织生长抑制作用,探讨其应用于肝癌基因治疗的可行性。方法:将人甲胎蛋白启动子控制表达HIVVpr基因的重组腺病毒(rvAdAFP-Vpr)直接注射到利用BEL-7402细胞建立的肝癌裸鼠模型瘤体内,同时往裸鼠腹腔内注射环磷酰胺(CTX),经过1个月的治疗,利用肿瘤生长曲线、增殖指数、凋亡指数等指标,观察rvAdAFP-Vpr对肝癌组织生长抑制的效果。结果:人甲胎蛋白启动子控制表达HIVVpr基因的重组腺病毒在肝癌组织中表达了Vpr蛋白,rvAdAFP-Vpr注射明显诱导肿瘤细胞凋亡,抑制了体内肝癌组织的生长,rvAdAFP-Vpr治疗组和rvAdAFP-Vpr+CTX治疗组抑瘤率分别达到41%和66.7%,与空白对照组和rvAd-null组相比,具有统计学意义,差异显著(P<0.05,P<0.01),两组的Ki-67指数和凋亡指数相比,对照组和空腺病毒载体(rvAd-null)组同样具有统计学意义,差异显著(P<0.05,P<0.01)。结论:人甲胎蛋白启动子控制表达HIVVpr基因的重组腺病毒rvAdAFP-Vpr通过引起肝癌细胞凋亡,有效抑制了体内肝癌组织的生长。本研究结果为HIV-1Vpr应用于肝癌治疗提供了依据。

Objective：To investigate the anti - hepatic carcinoma effects of recombinant adenovirus encoding HIV Vpr gene driven by human alpha fetoprotein （AFP） promoter （ rvAdAFP - Vpr） in nude mice and discuss the feasi- bility of using the recombinant adenovirus in the gene therapy of hepatic carcinoma. MethOdS： After transplantation of BEL -7402 hepatic carcinoma ceils in the liver, nude mice were injected with rvAdAFP - Vpr into the tumor tissues. Meanwhile, cycl,-phosphamide （CTX） was intraperitoneally injected. After one month of treatment, the inhibitory effect of rvAdAFP - Vpr on the growth of hepatoma was assessed by using the tumor growth curve, proliferation index, and apoptotic index. Results： The Vpr protein was expressed in hepatic carcinoma tissue after injection of rvAdAFP - Vpr. rvAdAFP - Vpr injection significantly induced tumor cell apoptosis and suppressed the growth of hepatoma in vivo. The tumor - suppressing rate was 41% in the rvAdAFP - Vpr group and 66.7% in the rvAdAFP - Vpr ＋ CTX group, and the rates in the two groups were significantly higher than those in the control group and the rvAd - null group （ P 〈 0.05, P 〈 0.01 ）. The Ki - 67 index and the apoptotic index were also significandy higher in the rvAdAFP - Vpr and rvAdAFP - Vpr ＋ CTX groups than those in the control and rvAd - null groups （ P 〈 0.05, P 〈 0.01 ）. Conclusion ： rvAdAFP - Vpr effectively suppresse the growth of hepatic carcinoma in vivo through inducing apoptosis of tumor ceils. The present study demonstrated the feasibility of using HIV - 1 - Vpr in the treatment of hepatic carcinoma.