Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, People's Republic of China.
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Cancer Gene Ther. 2016 Jun;23(6):168-77. doi: 10.1038/cgt.2016.11. Epub 2016 Apr 15.
Lung cancer, especially adenocarcinoma, is one of the leading causes of death in the world. Carcinoembryonic antigen (CEA), a superb non-small-cell lung cancer marker candidate, showed a beneficial effect in cancer therapy with oncolytic adenovirus in recent studies. Cancer-targeting dual gene-virotherapy delivers two therapeutic genes, linked by a connexon, in the replication-deficient vector instead of one gene so that they can work in common. In this study, we constructed a tumor-specific oncolytic adenovirus, CD55-TRAIL-IETD-MnSOD. The virus has the fusion protein complementary DNAs for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and for manganese superoxide dismutase (MnSOD) complementary DNA linked through a 4-amino acid caspase-8 cleavage site (IETD), and uses a CEA promoter to control virus E1A express. This is the first work to use a CEA promoter-regulated oncolytic adenovirus carrying two therapeutic genes for cancer research. Its targeting and anticancer capacity was evaluated by in vitro and in vivo experiments. The results indicated that CD55-TRAIL-IETD-MnSOD caused more cell apoptosis than CD55-TRAIL or CD55-MnSOD alone, or their combination in vitro, with low cytotoxicity of normal cells. In the A549 tumor xenograft model in nude mice, data showed that CD55-TRAIL-IETD-MnSOD could effectively suppress tumor growth than single gene groups, with no histological damage in liver, spleen or kidney tissues. Thus, the CEA-regulated dual-gene oncolytic virus CD55-TRAIL-IETD-MnSOD may be a novel potential therapy for lung cancer.
肺癌，尤其是腺癌，是世界上主要的死亡原因之一。癌胚抗原（CEA）是一种优秀的非小细胞肺癌标志物候选物，最近的研究表明，在溶瘤腺病毒的癌症治疗中具有有益的效果。肿瘤靶向双基因-病毒治疗将两个治疗基因通过连接子连接到复制缺陷型载体中，而不是一个基因，以便它们可以共同发挥作用。在这项研究中，我们构建了一种肿瘤特异性溶瘤腺病毒 CD55-TRAIL-IETD-MnSOD。该病毒具有肿瘤坏死因子相关凋亡诱导配体（TRAIL）和锰超氧化物歧化酶（MnSOD）的融合蛋白 cDNA，通过 4 个氨基酸半胱天冬酶-8 切割位点（IETD）连接，并使用 CEA 启动子来控制病毒 E1A 的表达。这是首次使用 CEA 启动子调控的携带两种治疗基因的溶瘤腺病毒进行癌症研究。通过体外和体内实验评估了其靶向性和抗癌能力。结果表明，CD55-TRAIL-IETD-MnSOD 比 CD55-TRAIL 或 CD55-MnSOD 单独或它们的组合在体外引起更多的细胞凋亡，而对正常细胞的细胞毒性较低。在裸鼠的 A549 肿瘤异种移植模型中，数据表明 CD55-TRAIL-IETD-MnSOD 能有效抑制肿瘤生长，比单基因组更有效，且对肝、脾或肾组织无组织学损伤。因此，CEA 调控的双基因溶瘤病毒 CD55-TRAIL-IETD-MnSOD 可能是一种治疗肺癌的新型潜在疗法。
