3月17日，基因治疗领域国际专业期刊《基因治疗》（Gene Therapy）在线发表了中科院上海生命科学研究院生化与细胞所刘新垣院士研究组关于“肿瘤的靶向基因-病毒治疗”（Cancer Targeting Gene-Viro-Therapy, CTGVT）策略的最新研究成果。
尽管癌症治疗领域在过去几十年中取得了较大的进展，肝癌仍然是所有恶性肿瘤中最难治愈的种类之一。根据美国国立卫生研究院癌症研究所“监察、流行病学和最终结果”(Surveillance, Epidemiology and End Results, SEER)数据库公布的1975-2006年度癌症统计综述，美国1999-2005年原发性肝癌及肝内胆管癌病人的5年相对存活率为13.0%，仅高于胰腺癌病人（5.7%）。肝细胞癌（Hepatocellular carcinoma, HCC）作为最常见类型的肝癌和世界第五最频发的恶性肿瘤，是造成癌症相关死亡的第三大原因。因此，急需开发高效及安全的肝癌治疗新方法为临床服务，而生物治疗是最有前景的备选方案之一。
刘新垣研究组博士研究生曹欣等以SV40 enhancer/AFP复合启动子控制腺病毒E1A的表达，并缺失腺病毒在正常细胞中复制必需而在肿瘤细胞中复制非必需的E1B 55K蛋白，构建了靶向甲胎蛋白（AFP）阳性肝癌的双调控溶瘤腺病毒载体Ad?AFP?E1A?E1B (Δ55) (简称Ad?AFP?D55)。与仅缺失E1B 55K蛋白的单调控溶瘤腺病毒ZD55（ONYX-015类似物）相比，Ad?AFP?D55不仅具有肝癌靶向性，对正常细胞的安全性也有所提高，对裸鼠全身系统给药后肝毒性明显低于ZD55。为了提高对肿瘤的杀伤能力，研究人员又将肿瘤坏死因子相关的凋亡诱导配体(TRAIL)基因表达框插入腺病毒基因组中，即构成双调控基因-病毒系统Ad?AFP?D55-TRAIL。双调控腺病毒载体Ad?AFP?D55及Ad?AFP?D55-TRAIL能选择性地在AFP阳性的肝癌细胞中复制，并引起宿主细胞的强烈自噬作用，而TRAIL基因的引入则可促肿瘤细胞的凋亡。双调控基因-病毒系统Ad?AFP?D55-TRAIL在体外和体内均显示出良好的抗肝癌活性，这是因为溶瘤病毒本身即有抗癌作用，作为载体它还能特异性地（即靶向性）在癌细胞中复制数百倍，使其所携带的基因也随之复制数百倍，表达量也大大提高；故CTGVT的抗癌作用大增，既比相应单独基因治疗的抗癌效果好，也比相应溶瘤病毒治疗的抗癌效果好，成为今后的发展方向。研究组提出的CTGVT现已成为国际热门课题，产业化的前景光明。
该课题得到了国家重点基础研究发展计划（973计划）、国家高技术研究发展计划（863计划）、国家自然科学基金项目、中国科学院知识创新工程重要方向项目和上海市科委项目的经费支持。（生物谷Bioon.com）
生物谷推荐原文出处：
Gene Therapy advance online publication 17 March 2011; doi: 10.1038/gt.2011.1
Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene
X Cao1, M Yang2, R-C Wei3, Y Zeng4, J-F Gu1, W-D Huang1, D-Q Yang1, H-L Li1,5, M Ding1, N Wei1, K-J Zhang1, B Xu6, X-R Liu1, Q-J Qian7,8 and X-Y Liu1,7
Liver cancer is a common and aggressive malignancy, but available treatment approaches remain suboptimal. Cancer targeting Gene-Viro-Therapy (CTGVT) has shown excellent anti-tumor effects in a preclinical study. CTGVT takes advantage of both gene therapy and virotherapy by incorporating an anti-tumor gene into an oncolytic virus vector. Potent anti-tumor activity is achieved by virus replication and exogenous expression of the anti-tumor gene. A dual-regulated oncolytic adenoviral vector designated Ad·AFP·E1A·E1B (Δ55) (Ad·AFP·D55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/α-fetoprotein (AFP) composite promoter (AFPep) based on an E1B-55K-deleted construct, ZD55. Ad·AFP·D55 showed specific replication and cytotoxicity in AFP-positive hepatoma cells. It also showed enhanced safety in normal cells when compared with the mono-regulated vector ZD55. To improve the anti-hepatoma activities of the virus, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene was introduced into Ad·AFP·D55. Ad·AFP·D55-TRAIL exhibited remarkable anti-tumor activities in vitro and in vivo. Treatment with Ad·AFP·D55-TRAIL can induce both autophagy owing to the Ad·AFP·D55 vector and caspase-dependent apoptosis owing to the TRAIL protein. Therefore, Ad·AFP·D55-TRAIL could be a potential anti-hepatoma agent with anti-tumor activities due to AFP-specific replication and TRAIL-induced apoptosis.
Keywords: cancer targeting Gene-Viro-Therapy; dual-regulated oncolytic adenovirus; tumor necrosis factor-related apoptosis-inducing ligand; autophagy; apoptosis
