Oncotarget:中科院上海巴斯德所周东明课题组发表新型溶瘤腺病毒
2017年4月18日，国际肿瘤学学术期刊《Oncotarget》杂志上在线发表了中国科学院上海巴斯德研究所周东明课题组的最新研究成果，题为A Novel Oncolytic Adenovirus Based On Simian Adenovirus Serotype 24。研究助理成涛为论文第一作者，周东明研究员为论文通讯作者。
近年来，溶瘤腺病毒因其创新性和疗效成为肿瘤治疗领域的热点。通常溶瘤腺病毒以人5型腺病毒(AdHu5)为载体，但人群中普遍存在针对AdHu5的中和抗体，影响其疗效;并且，AdHu5的Hexon蛋白与血液中的凝血因子X(FX)结合，导致该腺病毒在肝脏累积，影响AdHu5的肿瘤靶向性。因此，溶瘤腺病毒的效能和靶向性有待进一步提高和完善。由于黑猩猩型腺病毒如AdC7在人群中很少流行，人群中一般不存在相应的中和抗体，不会被针对AdHu5的抗体所中和，AdC7的Hexon蛋白也不与FX结合。因此，AdC7可发展为一种理想的溶瘤病毒载体平台。
研究人员构建了E3删除的重组腺病毒AdC7，并以肿瘤特异性survivin启动子替代腺病毒E1A启动子，构建成条件复制型腺病毒AdC7-SP/E1A-ΔE3。体外实验显示该溶瘤腺病毒能在多种肿瘤细胞中增殖，并且显著抑制NCI-H508和Huh7等肿瘤细胞的生长，而对正常细胞无损伤;荷瘤小鼠模型显示该溶瘤腺病毒通过瘤内注射或静脉给药都能显著拮抗结直肠癌和肺癌的发展。抑瘤机制研究表明该新型溶瘤腺病毒通过非P53依赖的线粒体凋亡通路产生抑瘤作用。该研究首次将黑猩猩型腺病毒改造成为溶瘤病毒，并证明其潜在的临床应用价值，为肿瘤临床治疗研究提供了新策略。
溶瘤腺病毒AdC7-SP/E1A-ΔE3对Huh7荷瘤小鼠的抑瘤作用
原文链接：
A Novel Oncolytic Adenovirus Based On Simian Adenovirus Serotype 24
原文摘要：
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.
作者：周东明
