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Gene therapy of peritoneal matastasis of GI cancer with a viral vector bearing a cytokine gene

Research Project

Project/Area Number 08457328
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionYokohama City University

Principal Investigator

AMANO Tomishige  Yokohama City University, School of Medicine, Instructor, 医学部, 講師 (20112485)

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)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsHerpes viral vector / Gene therapy / Interleukin-2 / Cytokine / Peritoneal metastasis of gastrointestinal cancer / Nude mice / Natural killer cell / ウイルスベクター
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.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Kawamoto, S.: "Expression of NMDR receptor channel proteins using bacuolo virus andherpes virus vectors" Methods in Molecular Biology. in press (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Noguchi, Y: "The possible role of TNF-α andinterleukin-2 in inducing tumor-associated metabolic alterations" Surgery Today. 26. 36-41 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Noguchi, Y.: "Are cytokines possible mediators of cancer cachexia?" Surgery Today. 26. 467-475 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 服部, 聡: "ウイルスベクターを用いた遺伝子治療" 歯界展望. 88. 1373-1385 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Doulet Marat.: "ヒト心筋におけるfacilitative glucose transporter mRNAの発現" 日本外科学会雑誌. 99. 59- (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawamoto, S.: "Gene Therapy" Friedmann T.,Mulligan R.,NabelG and Wetherall D. (Cold Spring Harbor Laboratory), 388 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 服部 聡: "ニューロサイエンスラボマニュアル2:神経生物学のための遺伝子導入発現研究法" 中川八郎,吉川和明(シュプリンガー・フェアラーク東京), 363 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawamoto S,Hattori S,Okuda K.: "Expression of NMDR receptor channel proreins using bacuolo virus and herpesvirus vectors." Methods in Molecular Biology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Noguchi Y,Makino T,Yoshikawa T,Nomura K,Matsumoto A,Yamada T.: "The possible role of TNF-alpha and interleukin-2 in inducing tumor-associated metabolic alterations." Surgery Today. 26. 36-41 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Noguchi Y,Yoshikawa T,Matsumoto A,Savaninger G,Gelin J.: "Are cytokines possible mediators of cancer cachexia?" Surgery Today. 26. 467-475 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hattori S,Kanno H,Tsuburaya A,Yamamoto I,Okuda K,Kawamoto S.: "Gene therapy with viral vector." Shikai Tenbo. 88. 1373-1385 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [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
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawamoto, S.: Gene Therapy. Friedmann T,Mulligan R,Nabel G,Wetherall D ed.Cold Spring Laboratory, (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hattori S.: Neuroscience lab manual 2 : Experimental methods of gene introduction for neuro-biology Nakagawa H,Yoshikawa K.ed.Springer, (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawamoto,S.: "Molecular functional analysis of the glutamate receptor channle subunits cxpressed in bacuolovirus and herpesvirus vector systems" Biochemical Society Transactions. 24・4. 567S (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tsuburaya,A.: "Treatment of peritoncal metastasis by a defective herpes simplex viral vector bearing Interleukin-2" AACR '98 Proceedings. (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Noguchi,Y.: "Tumor-associated metabolic alterations In patients with gastric and esophageal cancer (changes In lipoprotein lipase activity In cancer patients)" Hepato-gastroenterology. (In press).

    • Related Report
      1997 Annual Research Report
  • [Publications] 服部,聡: "欠損型ヘルペスウイルスベクターを用いたグルタミン酸受容体チャンネルの発現,解析" 生化学. 68・7. 866 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kawamoto,S.: "Expression of the NMDA receptor channel subunits using a bacuolovirus vector and defective herpes simplex virus vecotor" FEBS '96 Absract. 186 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yoshikawa,T.: "Cellular amd molecular mechanisms of insulin resistance in adipose cells from tumor-bearing rats" Surgical Forum. 7-8 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kawamoto,S.: "Gene Therapy" Friedmann,T., Mulligan,R., Nabel,G and Wetherall,D.(Cold Spring Harbor Laboratory), 388 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] 服部,聡: "ニューロサイエンスラボマニュアル2:神経生物学のための遺伝子導入発現研究法" 中川 八郎, 吉川和明 (シュプリンガー・フェアラーク東京), 363 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Noguchi Y: "Role of insulin resistance in decreasing lipoprotein lipase activity in tumor-bearing rats" Surgery Today. 26. 271-275 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Noguchi Y: "Are cytokines possible mediators of cancer cachexia?" Surgery Today. 26. 467-475 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Noguchi Y: "The possible role of TNF-α and Interleukin-2 in inducing tumor-associated metabolic alterations." Surgery Today. 26. 36-41 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sato Y: "Immunohistochemical localozation of facilitated-diffusion glucose transporters in rat pancreatic islet." Tissue & Cell. 28. 637-643 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nomura K: "The stimulation of decreased lipoprotein lipase activity in the tumor-bearing state by the anti-hyperlipidemic drug Bezafibrate" Surgery Today. 26. 89-94 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yoshikawa T: "Alimentary hyperglucemia in patients with subtotal gastrectomy is associated with decreased insulin secretion but not with insulin resistance" International Surgery. 81. 32-35 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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