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Experimental Efficacy of Adenovirus-mediated Gene Therapy for Gallbladder Cancer

腺病毒介导的胆囊癌基因治疗的实验疗效

基本信息

批准号：
13670489
负责人：
ABEI Masato
金额：
$ 2.24万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670489/
关键词：
gallbladder cancer gene therapy adenovirus

项目摘要

New treatments, such as gene therapy, are necessary for advanced gallbladder cancer (GBC) but little has been studied. Recent studies have introduced E1 mutant adenoviruses (Ads) which show tumor-specific replication and promising clinical results. To enhance the safety of this approach, we newly constructed AxdAdB-3, a double-restricted Ad with a mutant E1A and E1B-55kD deletion. We studied the in vitro and in vivo effects of this Ad on GBC as well as its safety for normal human cells in comparison with wild-type Ad or an E1B-55kD deleted Ad, AxE1AdB. AxdAdB-3 replicated in and caused oncolysis of several GBC cell lines as efficiently as wild-type Ad or AxE1AdB in vitro. By contrast, AxdAdB-3, replicated much less effectively in primary normal cells (e.g., epithelial cells, endothelial cells and hepatocytes) than in GBC cells and had only a mild cytopathic effects, unlike wild-type Ad. Furthermore, cytotoxicity of AxdAdB-3 in normal cells was milder than AxE1AdB. AxdAdB-3 significantly (p<0.01) suppressed the growth of GBC xenografts. AxdAdB-3 also showed therapeutic efficacy for mice with peritoneally disseminated GBC, showing tumor-selective replication and oncolysis that resulted in significantly (p<0.05) prolonged survival. The present study showed that- the El double-restricted Ad effectively and selectively replicates in and causes oncolysis of GBC in vitro and in vivo with reduced negative effects on normal cells, suggesting that this could be a promising gene therapy tool for GBC.

新的治疗方法，如基因治疗，对于晚期胆囊癌（GBC）是必要的，但研究很少。最近的研究引入了E1突变腺病毒（ad），它们显示出肿瘤特异性复制和有希望的临床结果。为了提高这种方法的安全性，我们新构建了AxdAdB-3，这是一个具有突变体E1A和E1B-55kD缺失的双限制性Ad。我们研究了这种Ad在体外和体内对GBC的影响，以及与野生型Ad或E1B-55kD缺失Ad AxE1AdB相比，它对正常人类细胞的安全性。AxdAdB-3在体外与野生型Ad或AxE1AdB一样有效地复制并引起几种GBC细胞系的溶瘤。相比之下，AxdAdB-3在原代正常细胞（如上皮细胞、内皮细胞和肝细胞）中的复制效率远低于在GBC细胞中的复制效率，并且与野生型Ad不同，AxdAdB-3仅具有轻微的细胞病变作用。此外，AxdAdB-3在正常细胞中的细胞毒性比AxE1AdB轻。AxdAdB-3显著（p<0.01）抑制GBC异种移植物的生长。AxdAdB-3对腹膜播散性GBC小鼠也有治疗作用，表现出肿瘤选择性复制和溶瘤，显著延长生存期（p<0.05）。本研究表明- El双限制性Ad在体外和体内均能有效、选择性地在GBC中复制并引起肿瘤溶解，对正常细胞的负面影响较小，这可能是一种很有前景的GBC基因治疗工具。