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

胰腺癌是日本最难治的癌症之一。为了在胰腺癌手术切除后获得良好的生存效益，采用体外实验和动物实验对自杀基因治疗和基因修饰免疫治疗进行了研究。将干扰素-γ与B7黏附分子(干扰素-伽马/B7/结肠癌26)共转染低免疫原性结肠腺癌细胞，作为刺激剂激活细胞毒性T淋巴细胞(CTL)。干扰素-γ/B7联合转染对内源性I类分子的上调作用和对CTL的诱导作用明显强于单独转染B7。经腹腔注射干扰素-γ/B7/Colon26可显著抑制皮下接种野生型Colon26的肿瘤生长，提示B7与干扰素-γ共转染作为肿瘤疫苗具有一定的应用价值。另一方面，利用6种阳离子脂质体、1种融合基因脂质体和1种腺病毒载体，比较了CEA启动子驱动的细胞因子脱氨酶自杀基因的体内外转染率和抗肿瘤效果。后两种载体在效率和毒副作用方面均优于任何阳离子脂质体。尽管β-半乳糖苷酶在转移瘤中有特异性表达，但通过阳离子脂质体介导的体内基因转导，前药5-FC对腹膜胰腺癌无抗肿瘤作用。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，需要更有效的前药物和旁观者效应的修饰。

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.