Development of multimodal gene therapy for gastrointestinal cancer using in vivo electroporation

制备了一种新的细胞因子白细胞介素21和白细胞介素23的cDNA。证实了将这些新的细胞因子基因转导到肿瘤细胞中可以诱导强大的肿瘤免疫。并且，对于使用裸鼠的人食管癌移植模型，也确认了IL-21的抗肿瘤活性的效果。检测了由肿瘤特异性微型启动子启动的HSV-tk基因的效用。HSV-tk基因治疗最有趣的效应是旁观者效应，这是一种允许杀死未转导细胞的现象。利用中期因子的最小启动子区驱动HSV-tk基因，通过体内电穿孔将IL-21 DNA导入肿瘤细胞，这一联合策略产生了一种有效的基因治疗方法，并改进safety.in体内电穿孔法，但其应用范围有限，临床应用范围较窄。体内电穿孔抗癌药物的临床试验 ...更多信息 地毯直到现在被用于仅限于皮下肿瘤。因此，研制出了一种可在纤维内窥镜下使用的新型电极，在猪模型中，在开胸或剖腹手术下对食管或肝脏进行体内电穿孔不会产生生理效应，可以安全地进行。这些结果有助于临床应用。改进后的电极既可在纤维内窥镜下使用，也可在镜下操作。目前，正在申请专利。与基因转移相结合，希望能获得很高的基因表达量，通过组蛋白去乙酰基转移酶抑制剂（FK 226）可以增强转染基因的转录。FK 226诱导了一个肿瘤抑制基因，我们证实了在人食管癌细胞中显示出抗肿瘤活性的效果。分析细胞因子基因的抗肿瘤效果的增强作用和通过使用FK 226的体内电穿孔的组合对疫苗的效果。少

The preparation of cDNA of interleukin-21 and-23 which is a new cytokine gene was done. It could confirm that powerful tumor immunity was induced by transducing these new cytokine genes to the tumor cells. And, as for human esophageal cancer transplantation model as well which a nude mice was used for, the effect on an anti-tumor activity of IL-21 was confirmed. The utility of the HSV-tk gene which is promoted by tumor specific mini-promoter was examined. The most interesting effect of HSV-tk gene therapy is the by-stander effect, a phenomenon allowing the killing of untransduced cells. By using the minimal promoter region of midkine to drive HSV-tk gene, and in vivo electroporation to transduce the IL-21 DNA into the tumors, this comibination strategy produces an efficient gene therapy with improved safety.in vivo electroporatio under the view adds a limitation to that utility and clinical application range gets narrow. The clinical trials of in vivo electroporation using anticancer d … More rugs until now was used for is limited to the subcutaneous tumor. Therfore the new electrode which could be used under the fiberscope was developed, in vivo electroporation to the esophagus or the liver under thoracotomy or laparotomy in swine model didn't give it a physiological effect and it could be carried out safely. These results caused to clinical application. The electrode which could be used by fiberscope or under the scopic operation was improved. And that prototype was completed.At present, an application for a patent is being prepared.As for the combination with the gene transfer, a very high gene expression is expected so that histone deacethyl taransferase inhibitor (FK226) may strengthen the transcription of the transfected gene. One of the tumor suppressor genes was induced by FK226, and we confirmed that effect on an anti-tumor activity was shown in the human esophageal cancer cells. It will be analyzed about the reinforcement action of the effect on an anti-tumor of cytokine genes and the effect on vaccine by the combination of in vivo electroporation using FK226. Less