A novel oncolytic adenovirus based on simian adenovirus serotype 24.
A novel oncolytic adenovirus based on simian adenovirus serotype 24.
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一种基于猿猴腺病毒血清型 24 的新型溶瘤腺病毒
DOI：
10.18632/oncotarget.15845
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发表时间：
2017-04-18
期刊：
影响因子：
--
通讯作者：
Zhou D
中科院分区：
文献类型：
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作者：
Cheng T;Song Y;Zhang Y;Zhang C;Yin J;Chi Y;Zhou D
溶瘤病毒疗法是一种新兴的肿瘤治疗方法，目前腺病毒在临床前和临床试验中被广泛应用。传统上，溶瘤腺病毒基于人腺病毒血清型5（AdHu 5）开发。然而，AdHu 5在大多数人群中具有预先存在的抗AdHu 5免疫的缺点，并且AdHu 5通过六邻体、凝血因子X（FX）和FX受体相互作用被肝脏广泛隔离。为了解决这些问题，我们探索了一种新的溶瘤腺病毒AdC 7-SP/E1 A-ΔE3用于癌症治疗。以猴腺病毒血清24型（AdC 7）为基础，采用直接克隆的方法，将E1 A启动子替换为肿瘤特异性启动子survivin启动子，缺失E3区，构建成AdC 7-SP/E1 A-ΔE3。我们发现AdC 7-SP/E1 A-ΔE3可显着杀死肿瘤细胞系NCI-H508和Huh 7，并抑制NCI-H508和Huh 7异种移植肿瘤模型中的肿瘤生长。重要的是，AdC 7-SP/E1 A-ΔE3通过全身给药表现出抗肿瘤功效。AdC 7-SP/E1 A-ΔE3通过非p53依赖的线粒体凋亡途径杀伤感染细胞，BAD磷酸化水平显著降低，Bik表达显著增加。因此，AdC 7-SP/E1 A-ΔE3是一种有希望的肝脏和结肠肿瘤治疗候选物。
Among the oncolytic virotherapy, an emerging treatment for tumor, adenoviruses are widely used at present in preclinical and clinical trials. Traditionally, oncolytic adenoviruses were developed based on the human adenovirus serotype 5 (AdHu5). However, AdHu5 has the drawbacks of preexisting anti-AdHu5 immunity in most populations, and extensive sequestration of Adhu5 by the liver through hexon, blood coagulation factor X (FX), and FX receptor interactions. To tackle these problems, we explored a novel oncolytic adenovirus AdC7-SP/E1A-ΔE3 for cancer treatment. AdC7-SP/E1A-ΔE3 was constructed by replacing the E1A promoter with tumor specific promoter survivin promoter and deleting E3 region using direct cloning methods based on simian adenovirus serotype 24 (namely AdC7). We showed that AdC7-SP/E1A-ΔE3 significantly killed tumor cell lines NCI-H508 and Huh7, and inhibited tumor growth in both NCI-H508 and Huh7 xenograft tumor models. Importantly, AdC7-SP/E1A-ΔE3 exhibited the antitumor efficacy via systemic administration. Mechanistically, infected cells were killed by AdC7-SP/E1A-ΔE3 via the p53-independent mitochondrial apoptosis pathway in which phosphorylation of BAD markedly declined and the expresses of Bik significantly went up. Therefore, AdC7-SP/E1A-ΔE3 is a promising candidate for liver and colon tumor treatment.