2004 Fiscal Year Final Research Report Summary
Development of multimodal gene therapy for gastrointestinal cancer using in vivo electroporation
| Project/Area Number |
14370377
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Chiba University |
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Principal Investigator |
MATSUBARA Hisairo Chiba Univ., Graduate School of Med., Assistant Professor, 大学院・医学研究院, 講師 (20282486)
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| Co-Investigator(Kenkyū-buntansha) |
OCHIAI Takenori Chiba Univ., Graduate School of Med., Professor, 大学院・医学研究院, 教授 (80114255)
GUNJI Yoshio Chiba Univ., Graduate School of Med., Associate Professor, 大学院・医学研究院, 助教授 (60241957)
TAGAWA Masatoshi Chiba Cancer Center, Research Inst., Director, 研究局, 部長 (20171572)
MIYAZAKI Shin-ichi Chiba Univ., University Hospital, Assistant Professor, 医学部附属病院, 助手 (40334198)
URASHIMA Tetsuro Chiba Univ., University Hospital, Assistant Professor, 医学部附属病院, 助手 (80375625)
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| Project Period (FY) |
2002 – 2004
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| Keywords | gene therapy / in vivo electroporation / gastrointestinal cancer / p53 gene / suicide gene / cytokine |
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| Research Abstract |
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
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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
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