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Suicide gene therapy and tumor specific CTL activated by B7 gene transfected tumor cells against pancretic cancer.

B7基因转染肿瘤细胞激活的自杀基因疗法和肿瘤特异性CTL对抗胰腺癌。

基本信息

批准号：
08457315
负责人：
KOBARI Masao
金额：
$ 4.8万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Pancreatic cancer is one of the most intractable cancer in Japan. In order to achieve a good survival benefit after surgical resection of pancreatic cancer, suicide gene therapy and genetically modified immunotherapy were examined using in vitro and animal experiments. Poorly immunogenic colon26 adenocarcinoma cells were co-transfected with interferon-gamma and B7 adhesion molecule (IFN-gamma/B7/colon26) and utilized as a stimurant to activate cytotoxic T lymphocytes (CTL). The upregulation effect of the endogenous class I molecules and induction of CTL by IFN-gamma/B7 co-transfection appreared to be much stronger than the transfection of B7 alone. The result that intraperitoneal injections with IFN-gamma/B7/colon26 significantly prevented the tumor growth of subcutaneously inoculated wild type colon26 implies the usefulness of co-transfection of B7 and IFN-gamma as a tumor vaccine. On the other hand, in vitro and in vivo transfection efficiency and anti-tumor effects of cytocine deaminase suicide gene driven by CEA promoter was compared using six cationic liposomes, a fusogenic liposome and an adenoviral vector. The latter two vectors were superior to any cationic liposomes in the viewpoint of efficiency and adverse toxicity. No antitumor effects of prodrug 5-FC against peritoneal pancreatic cancer was obtained by in vivo gene transduction mediated by cationic liposome although beta galactosidase was expressed specifically within the disseminated tumors. These data suggests that viral vector and fusogenic liposome might be utilized as an in vivo gene transducer and that more potent pro-drug and modification of by-stander effects are required.

胰腺癌是日本最难治的癌症之一。为了获得胰腺癌手术切除后良好的生存效益，采用体外和动物实验对自杀基因治疗和转基因免疫治疗进行了研究。将免疫原性差的colon 26腺癌细胞与干扰素-γ和B7粘附分子（IFN-γ/B7/colon 26）共转染，并用作刺激剂以激活细胞毒性T淋巴细胞（CTL）。IFN-γ/B7共转染的内源性I类分子的上调作用和CTL诱导作用明显强于单独转染B7。腹膜内注射IFN-γ/B7/colon 26显著防止皮下接种的野生型colon 26的肿瘤生长的结果暗示了B7和IFN-γ的共转染作为肿瘤疫苗的有用性。另一方面，在体外和体内的转染效率和抗肿瘤效果进行了比较，由CEA启动子驱动的胞嘧啶脱氨酶自杀基因使用六个阳离子脂质体，融合脂质体和腺病毒载体。后两种载体在效率和不良毒性方面上级任何阳离子脂质体。尽管β-半乳糖苷酶在播散性肿瘤中特异性表达，但阳离子脂质体介导的体内基因转导未获得前体药物5-FC对腹膜胰腺癌的抗肿瘤作用。这些数据表明，病毒载体和融合脂质体可能被用作体内基因转导器，并且需要更有效的前药和改变旁观者效应。