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Oncolytic adenovirus modified to increase its infectivity for gastrointestinal cancer

溶瘤腺病毒经过修饰以增加其对胃肠道癌症的感染性

基本信息

批准号：
16591381
负责人：
TAGAWA Masatoshi
金额：
$ 2.3万
依托单位：
Chiba Cancer Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Adenovirus (Ad) has a strong cytotoxic activity and the E1A protein, one of the early transcriptional products, has a pivotal role in viral replication in the infected cells. Ad modified to control the E1A gene expression with a putative tumor promoter can thereby be oncolytic. We examined the regulatory regions of the genes which were predominantly expressed in tumors with the luciferase assay and found that a 500 bp and a 600 bp upstream regions of the survivin and midkine genes, respectively, were responsible for the transcriptional control. The cellular receptors of the Ad type 5 is CAR (Coxsackievirus and Adenovirus Receptor) and the expression is often downregulated in gastrointestinal tumors. In contrast, the expression of CD46, which is a receptor of Ad type 35, is rather upregulated in the tumors and consequently, the Ad bearing CD46 binding sites can increase the infectivity to the tumors. We thereby constructed a vector system consisting of vector DNA that could activate the E1A and E1B genes with an exogenous regulatory region and another vector that contained the rest of the whole Ad sequences, in which the fiber-knob region was replaced with the Ad type 35-derived one. In vitro ligation of the vectors enables the construction of the Ad bearing the type 35 fiber-knob structure in the E3 region. The oncolytic Ad with the type 35 fiber-knob can be produced with easy compared with conventional methods that required in vivo recombination. The chimeric oncolytic Ad prepared with our vector system was more cytotoxic to CAR-low human tumors than conventional type 5 oncolytic Ad and was as cytotoxic as the type 5 Ad to CAR-high tumors.

腺病毒(Ad)具有很强的细胞毒活性，其早期转录产物E1a蛋白在病毒在感染细胞中的复制中起着关键作用。因此，用假定的肿瘤启动子来控制E1a基因表达的腺病毒载体可以溶解肿瘤。我们用荧光素酶分析法检测了在肿瘤中主要表达的基因的调控区，发现Survivin和Midkine基因上游分别有500bp和600bp的区域负责转录控制。Ad5的细胞受体是柯萨奇病毒和腺病毒受体(CAR)，在胃肠道肿瘤中表达下调。而作为Ad35受体的CD46在肿瘤中的表达明显上调，因此携带CD46结合位点的Ad可以增加肿瘤的感染性。因此，我们构建了一个载体系统，其中一个载体DNA可以激活带有外源调控区的E1a和E1B基因，另一个载体包含其余的完整Ad序列，其中纤维结区被Ad35型衍生的纤维结区所取代。通过体外连接载体，可以在E3区构建具有35型纤维结节结构的重组腺病毒。与需要体内重组的传统方法相比，具有35型纤维结节的溶瘤Ad可以更容易地制备出来。用我们的载体系统制备的嵌合溶瘤Ad对人肝癌细胞的杀伤作用比传统的5型溶瘤Ad更强，而对人肝癌的杀伤作用与5型溶瘤Ad相当。

项目成果

期刊论文数量（92）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vaccination of apoptotic Fas ligand-expressing tumors decreased antitumor responses by enhanced production of immunosuppressive cytokines.

表达凋亡 Fas 配体的肿瘤的疫苗接种可通过增强免疫抑制细胞因子的产生来降低抗肿瘤反应。

DOI：
发表时间：
2005
期刊：
Anticancer Res. 25
影响因子：
0
作者：
Wada A;Tagawa M et al.
通讯作者：
Tagawa M et al.

Elevated expression of DNA polymerase x expression in human lung cancer is associated with p53 inactivation: Negative regulation of POLKpromoter activity by p53.

人肺癌中 DNA 聚合酶 x 表达的升高与 p53 失活相关：p53 对 POLK 启动子活性的负调节。

DOI：
发表时间：
2004
期刊：
Int.J.Oncol. 25
影响因子：
0
作者：
Wang;Y.Q.;Seimiya;M.;Kawamura;K.;Yu;L.;Ogi;T.;Takenaga;K.;Shishikura;T.;Nakagawara;A.;Sakiyama;S.;Tagawa;M.;O-Wang;J.
通讯作者：
J.

Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer