Li Gongchu, Wu Hu, Cui Lianzhen, Gao Yajun, Chen Lei, Li Xin, Liang Tianxiang, Yang Xinyan, Cheng Jianhong, Luo Jingjing
College of life sciences, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China.
Oncotarget. 2015 Dec 22;6(41):43496-507. doi: 10.18632/oncotarget.6292.
Our previous studies have suggested that harboring a soluble coxsackie-adenovirus receptor-ligand (sCAR-ligand) fusion protein expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting to serotype 5 adenovirus infection. We report here a novel oncolytic adenovirus vector redirected to CD47+ leukemia cells though carrying a sCAR-4N1 expression cassette in the viral genome, forming Ad.4N1, in which 4N1 represents the C-terminal CD47-binding domain of thrombospondin-1. The infection and cytotoxicity of Ad.4N1 in leukemia cells were determined to be mediated by the 4N1-CD47 interaction. Ad.4N1 was further engineered to harbor a gene encoding melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), forming Ad.4N1-IL24, which replicated dramatically faster than Ad.4N1, and elicited significantly enhanced antileukemia effect in vitro and in a HL60/Luc xenograft mouse model. Our data suggest that Ad.4N1 could act as a novel oncolytic adenovirus vector for CD47+ leukemia targeting gene transfer, and Ad.4N1 harboring anticancer genes may provide novel antileukemia agents.
我们之前的研究表明，在病毒基因组中携带可溶性柯萨奇病毒 - 腺病毒受体配体（sCAR - 配体）融合蛋白表达盒，可能提供一种通用方法，使溶瘤腺病毒重新靶向抵抗5型腺病毒感染的癌细胞上的各种膜受体。我们在此报告一种新型的溶瘤腺病毒载体，它通过在病毒基因组中携带sCAR - 4N1表达盒而重新靶向CD47 +白血病细胞，形成Ad.4N1，其中4N1代表血小板反应蛋白 - 1的C末端CD47结合结构域。确定Ad.4N1在白血病细胞中的感染和细胞毒性是由4N1 - CD47相互作用介导的。Ad.4N1进一步被改造以携带编码黑色素瘤分化相关基因 - 7/白细胞介素 - 24（mda - 7/IL - 24）的基因，形成Ad.4N1 - IL24，其复制速度比Ad.4N1快得多，并在体外和HL60/Luc异种移植小鼠模型中引发显著增强的抗白血病作用。我们的数据表明，Ad.4N1可作为一种新型的针对CD47 +白血病靶向基因转移的溶瘤腺病毒载体，携带抗癌基因的Ad.4N1可能提供新型抗白血病药物。
