1997 Fiscal Year Final Research Report Summary
Gene therapy of peritoneal matastasis of GI cancer with a viral vector bearing a cytokine gene
| Project/Area Number |
08457328
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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 | Yokohama City University |
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Principal Investigator |
AMANO Tomishige Yokohama City University, School of Medicine, Instructor, 医学部, 講師 (20112485)
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| Co-Investigator(Kenkyū-buntansha) |
NOGUCHI Yoshikazu Yokohama City University, University Hospital, Instructor, 医学部・附属病院, 講師 (50180724)
HATTORI Satoshi Yokohama City University, School of Medicine, Assistant, 医学部, 助手 (40275037)
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| Project Period (FY) |
1996 – 1997
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| Keywords | Herpes viral vector / Gene therapy / Interleukin-2 / Cytokine / Peritoneal metastasis of gastrointestinal cancer / Nude mice / Natural killer cell |
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| Research Abstract |
Defective viral vector derived from herpes simplex virus type I (HSV) was tested in tumor cells and in an animal-tumor model of peritoneal metastasis of gastrointestinal carcinomas. Target genes were inserted at the cloning site adjacent a CMV promoter in the HSV vector, including lacZ as a marker gene, human IL-2 as a therapeutic gene and its anti-sense as a control. Infection of HSV and efficacy of the gene introduction were evaluated and improved in this system.
In vitro two cell lines established from human gastric cancer (MKN45 and MKN28) were incubated with HSV bearing IL-2 (HSV/IL-2) and IL-2 production in the media was measured by an ELISA.Both cells produced high levels of IL-2 parallel to the rate of infection. In the culture with high concentration of the vectors cytotoxic effects on the tumor cells were also observed. Gene introduction into immune cells is now under investigation.
In vivo a model of peritoneal metastasis was established in nude mice implanted with MKN45 cells in the peritoneal cavity. Ex vivo treated tumor cells with HSV/IL-2 did not grow in the peritoneum, while none of the animals surviced when treated with HSV bearing the anti-sense. Single injection of HSV/IL-2 cured 50% or 25% of the mice treated at 7 days or 14 days after tumor implantation, respectively. In the mice treated with HSV/IL-2 immunological parameters such as natural killer (NK) activity, serum IL-2, and interferon-gamma were markedly augmented. The therapeutic effects were attributed to NK cells since it was abolished by the blocker of NK cells (anti-acialo GM1 antibody), and the mice did not acquire a memory for the tumor.
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[Publications] Marat D,Noguchi Y,Uranaka Y,Yoshikawa T,Doi C,Okamoto T,Fukuzawa K,Makino T,Tsuburaya A,Imoto K,Kondo J.: "Expression of facilitative glucose transporter mRNA in human heart muscle." Jpn J Surg Asoc. 99. 59 (1998)
Description
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