3月17日,，基因治療領(lǐng)域國際專業(yè)期刊《基因治療》（Gene Therapy）在線發(fā)表了中科院上海生命科學(xué)研究院生化與細(xì)胞所劉新垣院士研究組關(guān)于“腫瘤的靶向基因-病毒治療”（Cancer Targeting Gene-Viro-Therapy, CTGVT）策略的最新研究成果。
盡管癌癥治療領(lǐng)域在過去幾十年中取得了較大的進(jìn)展,，肝癌仍然是所有惡性腫瘤中最難治愈的種類之一,。根據(jù)美國國立衛(wèi)生研究院癌癥研究所“監(jiān)察,、流行病學(xué)和最終結(jié)果”(Surveillance, Epidemiology and End Results, SEER)數(shù)據(jù)庫公布的1975-2006年度癌癥統(tǒng)計綜述，美國1999-2005年原發(fā)性肝癌及肝內(nèi)膽管癌病人的5年相對存活率為13.0%,，僅高于胰腺癌病人（5.7%）,。肝細(xì)胞癌（Hepatocellular carcinoma, HCC）作為最常見類型的肝癌和世界第五最頻發(fā)的惡性腫瘤，是造成癌癥相關(guān)死亡的第三大原因,。因此,，急需開發(fā)高效及安全的肝癌治療新方法為臨床服務(wù)，而生物治療是最有前景的備選方案之一,。
劉新垣研究組博士研究生曹欣等以SV40 enhancer/AFP復(fù)合啟動子控制腺病毒E1A的表達(dá)，并缺失腺病毒在正常細(xì)胞中復(fù)制必需而在腫瘤細(xì)胞中復(fù)制非必需的E1B 55K蛋白,，構(gòu)建了靶向甲胎蛋白（AFP）陽性肝癌的雙調(diào)控溶瘤腺病毒載體Ad?AFP?E1A?E1B (Δ55) (簡稱Ad?AFP?D55),。與僅缺失E1B 55K蛋白的單調(diào)控溶瘤腺病毒ZD55（ONYX-015類似物）相比,，Ad?AFP?D55不僅具有肝癌靶向性，對正常細(xì)胞的安全性也有所提高,，對裸鼠全身系統(tǒng)給藥后肝毒性明顯低于ZD55,。為了提高對腫瘤的殺傷能力，研究人員又將腫瘤壞死因子相關(guān)的凋亡誘導(dǎo)配體(TRAIL)基因表達(dá)框插入腺病毒基因組中,，即構(gòu)成雙調(diào)控基因-病毒系統(tǒng)Ad?AFP?D55-TRAIL,。雙調(diào)控腺病毒載體Ad?AFP?D55及Ad?AFP?D55-TRAIL能選擇性地在AFP陽性的肝癌細(xì)胞中復(fù)制，并引起宿主細(xì)胞的強(qiáng)烈自噬作用,，而TRAIL基因的引入則可促腫瘤細(xì)胞的凋亡,。雙調(diào)控基因-病毒系統(tǒng)Ad?AFP?D55-TRAIL在體外和體內(nèi)均顯示出良好的抗肝癌活性，這是因為溶瘤病毒本身即有抗癌作用,，作為載體它還能特異性地（即靶向性）在癌細(xì)胞中復(fù)制數(shù)百倍,，使其所攜帶的基因也隨之復(fù)制數(shù)百倍，表達(dá)量也大大提高,；故CTGVT的抗癌作用大增,，既比相應(yīng)單獨(dú)基因治療的抗癌效果好，也比相應(yīng)溶瘤病毒治療的抗癌效果好,，成為今后的發(fā)展方向,。研究組提出的CTGVT現(xiàn)已成為國際熱門課題，產(chǎn)業(yè)化的前景光明,。
該課題得到了國家重點(diǎn)基礎(chǔ)研究發(fā)展計劃（973計劃）,、國家高技術(shù)研究發(fā)展計劃（863計劃）、國家自然科學(xué)基金項目,、中國科學(xué)院知識創(chuàng)新工程重要方向項目和上海市科委項目的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
生物谷推薦原文出處：
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
