Gene therapy for gastrointestinal tumors with adenovirus in which the fiber-knob region was replaced

用腺病毒治疗胃肠道肿瘤，其中纤维旋钮区域被替换

基本信息

批准号：
17590692
负责人：
KAWAMURA Kiyoko
金额：
$ 2.24万
依托单位：
Chiba Cancer Center 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：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Adenoviruses (Ad) produce cytotoxic activities and potentially can destroy the infected cells. Ad which are used for gene transduction belong to the type 5 and use the coxsackievirus-adenovirus receptor (CAR) for their cellular receptors. Gastrointestinal tumors including pancreatic tumors however often express the CAR at low levels and consequently the transduction efficacy with the type 5 Ad remained low. On the other hand, type 35 Ad, belonging to the subtype B2 Ad, use CD46 as the cellular receptors, which is expressed at greater levels in tumors than in normal tissues. Since the receptor binding regions are localized in the fiber-knob region (E3-E4), replacement of the type 5 region with the type 35 could achieve better transduction efficacy. We thereby constructed a vector system to produce type 5 Ad bearing the type 35 fiber-knob region and found that the fiber-knob-replaced Ad enabled better transduction efficacy than the prototype 5 in most of tumors tested ; however, our further analyses showed that the efficacy was not directly correlated with the CD46 expression level in pancreatic tumors. We also produced a vector system in which the expression of ElA and E1B, immediate early genes with transcriptional activities, was controlled by exogenous promoters that were active in tumors. The fiber-knob-modified viruses whose ElA and ElB were regulated by the exogenous promoters could induce tumor cell-death with better efficacy than those bearing the type 5 fiber-knob region. The fiber modification however did not improve the efficacy in the CAR-high tumors. Further investigations also showed that the cytotoxic effects were not linked with the ElA protein expression levels and that the effects could be influenced by the cellular factor such as NF-1, which determined the Ad replication activity in the target cells.

腺病毒 (Ad) 产生细胞毒活性，并可能破坏受感染的细胞。用于基因转导的Ad属于5型并使用柯萨奇病毒-腺病毒受体(CAR)作为其细胞受体。然而，包括胰腺肿瘤在内的胃肠道肿瘤通常以低水平表达 CAR，因此 5 型 Ad 的转导功效仍然较低。另一方面，属于B2 Ad亚型的35型Ad使用CD46作为细胞受体，其在肿瘤中的表达水平高于正常组织。由于受体结合区域位于纤维旋钮区域（E3-E4），因此用 35 型区域替换 5 型区域可以实现更好的转导效果。因此，我们构建了一个载体系统来产生带有 35 型纤维旋钮区域的 5 型 Ad，并发现在大多数测试的肿瘤中，纤维旋钮取代的 Ad 比原型 5 具有更好的转导功效；然而，我们的进一步分析表明，疗效与胰腺肿瘤中CD46的表达水平并不直接相关。我们还生产了一个载体系统，其中具有转录活性的立即早期基因E1A和E1B的表达受到在肿瘤中活跃的外源启动子的控制。 ElA和ElB受外源启动子调控的纤维节修饰病毒可以比带有5型纤维节区域的病毒更有效地诱导肿瘤细胞死亡。然而，纤维修饰并没有提高 CAR 高肿瘤的疗效。进一步的研究还表明，细胞毒性作用与ElA蛋白表达水平无关，并且该作用可能受到诸如NF-1等细胞因子的影响，NF-1决定了靶细胞中Ad复制活性。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The effects of FasL on inflammation and tumor survival are dependent on its

FasL 对炎症和肿瘤存活的影响取决于其

DOI：
发表时间：
2007
期刊：
Cancer Gene Ther.
影响因子：
0
作者：
Wada A.;Tada Y;Kawamura K.;Takiguchi Y;Tatsumi K.;Kuriyama T.;Takenouchi T.;O-Wang J.;Tagawa M.
通讯作者：
Tagawa M.

DNA polymerase θ contributes to the θ generation of C/G mutations during somatic hypermutation of Ig genes.

DNA 聚合酶 θ 有助于 Ig 基因体细胞超突变期间 C/G 突变的 θ 产生。

DOI：
发表时间：
2005
期刊：
Proc. Natl. Acad. Sci. USA 102
影响因子：
0
作者：
Masuda;K.
通讯作者：
K.

Increased infectivity of adenovirus type 5 bearing type 11 or type 35 fibers to human esophageal and oral carcinoma cells.

DOI：
10.3892/or.14.4.831
发表时间：
2005-10
期刊：
Oncology reports
影响因子：
4.2
作者：
Ling Yu;H. Takenobu;O. Shimozato;K. Kawamura;Y. Nimura;N. Seki;K. Uzawa;H. Tanzawa;H. Shimada;T. Ochiai;M. Tagawa
通讯作者：
Ling Yu;H. Takenobu;O. Shimozato;K. Kawamura;Y. Nimura;N. Seki;K. Uzawa;H. Tanzawa;H. Shimada;T. Ochiai;M. Tagawa

Transcriptional regulatory regions of the survivin gene activate an exogenous suicide gene human tumors and enhance the sensitivity to a prodrug.

生存素基因的转录调控区激活人类肿瘤的外源自杀基因并增强对前药的敏感性。