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Inhibition of intrahepatic metastasis of hepatocellularcarcinoma by novel pyrrolidine derivatives

Research Project

Project/Area Number 19591578
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionThe University of Tokyo

Principal Investigator

KARAKO Takashi  The University of Tokyo, 医学部・附属病院, 助教 (00313213)

Co-Investigator(Kenkyū-buntansha) MAKUUCHI Masatoshi  東京大学, 医学部・附属病院, 名誉教授 (60114641)
NAKATA Munehiro  東海大学, 工学部, 教授 (00266371)
Project Period (FY) 2007 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords肝臓外科学 / 肝細胞癌 / 肝内転移 / 化学療法 / ピロリジン誘導体 / 治療
Research Abstract

本研究では、癌細胞の浸潤や転移において重要な役割をもつマトリクス・メタロプロテイナーゼ(MMP)の活性を阻害することが可能な新規ピロリジン誘導体を合成し、その有効性を検討することを目的とした。研究代表者らと共に山東大学「中・日新薬スクリーニングセンター」を設立した研究協力者によって、本研究計画において多くの種類の新規ピロリジン誘導体が合成され、有効な化合物のスクリーニングが実施された。その結果、合成された新規ピロリジン誘導体の一種であるLY52が、他の細胞に毒性を示すことなく、乳癌細胞MDA-MB-231の増殖を有意に阻害することを見出した。また、当該化合物は、化合物設計時の想定どおり、ターゲットとするMMP-2の酵素活性を有意に阻害した。さらに、癌培養細胞株を用いたin vitro解析により、当該化合物が癌細胞の浸潤を有意に阻害することが明らかとなった。また、癌を移植したモデルマウスを用いたin vivo実験では、当該化合物の経口投与により肺に形成される腫瘍結節数が有意に減少した。以上のことから、新規ピロリジン誘導体LY52は、癌細胞の増殖のほか、間質組織への浸潤及び他の臓器への転移を阻害することができ、抗癌効果をもつ化合物として有効であることが示唆された。
一方、本研究計画では、抗癌効果をもつことが明らかとなった化合物の構造に基づいて、その結果を化合物設計にフィードバックさせて更なる新規化合物の設計及び化合物ライブラリの拡大を図ってきた。現在、MMPのように癌の進行に重要なタンパク質分解酵素をターゲットとして設計した新規化合物群を有するライブラリが構築された。従って、本研究計画による成果は、今後のタンパク質分解酵素をターゲットとした創薬研究に対して大きく貢献することができたと考えている。

Report

(3 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • Research Products

    (27 results)

All 2008 2007

All Journal Article (19 results) (of which Peer Reviewed: 19 results) Presentation (8 results)

  • [Journal Article] Galloyl cyclic-imide derivativeCH1104I inhibits tumor invasionthrough suppressing matrixmetalloproteinase activity2008

    • Author(s)
      Chen MH, Cui SX, Cheng YN, Sun LR, LiQB, Xu WF, Ward SG, Tang W, Qu XJ
    • Journal Title

      Anticancer Drugs 19

      Pages: 957-965

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of new sulfonylpyrrolidine derivatives as matrixmetalloproteinase inhibitors2008

    • Author(s)
      Cheng XC, Wang Q, Fang H, Tang W, Xu WF
    • Journal Title

      BioorgMed Chem 16

      Pages: 7932-7938

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Design, synthesis and evaluationof novel sulfonyl pyrrolidinederivatives as matrixmetalloproteinase inhibitors2008

    • Author(s)
      Cheng XC, Wang Q, Fang H, Tang W, Xu WF
    • Journal Title

      BioorgMed Chem 16

      Pages: 5398-5404

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Strategies to overcome orcircumvent p-glycoprotein mediatedmultidrug resistance2008

    • Author(s)
      Yuan H, Li X, Wu J, Li J, Qu X, Xu W, Tang W
    • Journal Title

      Curr Med Chem 15

      Pages: 470-476

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Galloyl cyclic-imide derivative CH1104I inhibits tumor invas ion through suppressing matrix metalloproteinase activity.2008

    • Author(s)
      Chen MH, Cui SX, Cheng YN, Sun LR et al.
    • Journal Title

      Anticancer Drugs 19

      Pages: 957-965

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Positive KL-6 mucin expression combined with decreased membr anous β-catenin expression indicates worse prognosis in colo rectal carcinoma.2008

    • Author(s)
      Zhang W, Tang W, Inagaki Y, Qiu M et al.
    • Journal Title

      Ohcol Rep 20

      Pages: 1013-1019

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of new sulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors.2008

    • Author(s)
      Cheng XC, Wang Q, Fang H, T ang W, Xu WF
    • Journal Title

      Bioorg Med Chem 16

      Pages: 7932-7938

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design, synthesis and evaluation of novel sulfonyl pyrrolidine derivatives as matrix metalloproteinase inhibitors.2008

    • Author(s)
      Cheng XC, Wang Q, Fang H, T ang W, Xu WF
    • Journal Title

      Bioorg Med Chem 16

      Pages: 5398-5404

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Strategies to overcome or circumvent p-glycoprotein mediated multidrug resistance.2008

    • Author(s)
      Yuan H, Li X, Wu J, Li J, Qu X, Xu W, Tang W
    • Journal Title

      Curr Med Chem 15

      Pages: 470-476

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Design, synthesis and preliminary evaluation of novel pyrrolidine derivatives as matrix metalloProteinase inhibitors2008

    • Author(s)
      Cheng XC, Wang Q, Fang H, Tang W, Xu WF
    • Journal Title

      Eur J Med Chem (掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of human gastriccarcinoma cell growth by treatment ofN(3)-o-toluyl-fluorouracil as aprecursor of 5-fluorouracil2007

    • Author(s)
      Liu J, Li X, Cheng YN, Cui SX, Chen MH, Xu WF, Tian ZG, Makuuchi M, Tang W, QuXJ
    • Journal Title

      Eur Jpharmacol574 2007

      Pages: 1-7

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Induction ofapoptosis in human hepatocellularcarcinoma cells by syntheticantineoplaston A102007

    • Author(s)
      Qu XJ, Cui SX, Tian Z, Li X, Chen MH, Xu WF, Inagaki Y, Deng YB, Makuuchi M, Nakata M, Tang W
    • Journal Title

      Anticancer Res 27

      Pages: 2427-2431

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] KL-6mucin is a useful immunohistochemicalmarker for cholangiocarcinoma2007

    • Author(s)
      Tang W, Guo Q, Qu XJ, Inagaki Y, SeyamaY, Midorikawa Y, Gai R, Kokudo N, Sugawara Y, Nakata M, Makuuchi M
    • Journal Title

      Oncol Rep 17

      Pages: 737-741

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Recentadvances in P-gp-mediated MDRreversal mechanisms2007

    • Author(s)
      Li X, Qu XJ, Xu WF, Tang W
    • Journal Title

      Methods Find ExpClin Pharmacol 29

      Pages: 607-617

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Subcellular localizationof KL-6 mucin in colorectal carcinomacell lines : association withmetastatic potential and cellmorphology2007

    • Author(s)
      Guo Q, Tang W, Inagaki Y, Kokudo N, Sugawara Y, Karako H, Nakata M, Makuuchi M
    • Journal Title

      Oncol Rep 17

      Pages: 1057-1060

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] KL-6 mucin is a useful immunohistochemical marker for cholangiocarcinoma2007

    • Author(s)
      Tang W, 他6名, Kokudo N, Sugawara Y, Nakata M, Makuuchi M
    • Journal Title

      Oncol Rep 17

      Pages: 737-741

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of human gastric carcinoma cell growth by treatment of N(3)-o-toluyl-fluorouracil as a precursor of 5-fluorouracil2007

    • Author(s)
      Liu J, 他6名, Makuuchi M, Tang W, Qu XJ
    • Journal Title

      Eur J Pharmacol 574

      Pages: 1-7

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recent advances in P-glycoprotein-mediated multidrug resistance reversal mechanisms2007

    • Author(s)
      Li X, Li JP, Yuan HY, Gao X, Qu XJ, Xu WF, Tang W
    • Journal Title

      Methods Find Exp Clin Pharmacol 29

      Pages: 607-617

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Demographic and clinical characteristics of resectable hepatocellular carcinoma in China and Japan2007

    • Author(s)
      Yuan P, Tang W, 他12名, Makuuchi M
    • Journal Title

      Hepato-Gastroenterol 54

      Pages: 2343-2347

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] ANTINEOPLASTONA10 INHIBITS THE GROWTH OF HEPATOMACELLS THROUGH THE INDUCTION OFAPOPTOSIS2008

    • Author(s)
      Inagaki Y, Tang W, Qu XJ, Cui SX, LiX, Yuan YX, Tian ZG, Xu WF, Nakata M, Sugawara Y, Kokudo N
    • Organizer
      13th World Congress onAdvances in Oncology and 11thInternational Symposium on MolecularMedicine
    • Place of Presentation
      Crete, Greece
    • Year and Date
      2008-10-10
    • Related Report
      2008 Final Research Report
  • [Presentation] ANTINEOPLASTON A10 INHIBITS THE GROWTH OF HEPATOMA CELLS THROUGH THE INDUCTION OF APOPTOSIS.2008

    • Author(s)
      Inagaki Y, Tang W, Qu XJ, Cui SX et al.
    • Organizer
      13th World Congress on Advances in Oncology and 11th International Symposium on Molecular Medicine
    • Place of Presentation
      ギリシャ、クレタ島
    • Year and Date
      2008-10-09
    • Related Report
      2008 Annual Research Report
  • [Presentation] Different expression profile of KL-6mucin in primary liver cancer tissues2008

    • Author(s)
      Tang W, Inagaki Y, Xu HL, Seyama Y, Nakata M, Sugawara Y, Kokudo N
    • Organizer
      第108回日本外科学会定期学術集会
    • Place of Presentation
      長崎, 日本
    • Year and Date
      2008-05-16
    • Related Report
      2008 Final Research Report
  • [Presentation] Different expression profile of KL-6 mucin in primary liver cancer tissues.2008

    • Author(s)
      Tang W, Inagaki Y, Xu HL, Seynma Y et al
    • Organizer
      第108回日本外科学会定期学術集会
    • Place of Presentation
      日本、長崎
    • Year and Date
      2008-05-16
    • Related Report
      2008 Annual Research Report
  • [Presentation] Availability of KL-6 mucin as a tool for discriminating cholangiocarcinoma from hepatocellular carcinoma2007

    • Author(s)
      Inagaki Y, Xu HL, Kokudo N, Sugawara Y, Nakata M, Tang W
    • Organizer
      第30回日本分子生物学会年会・第80回日本生化学会合同大会
    • Place of Presentation
      神奈川県横浜市
    • Year and Date
      2007-12-14
    • Related Report
      2007 Annual Research Report
  • [Presentation] Availability ofKL-6 mucin as a tool fordiscriminating cholangiocarcinomafrom hepatocellular carcinoma2007

    • Author(s)
      Inagaki Y, Xu HL, Kokudo N, SugawaraY, Nakata M, Tang W
    • Organizer
      Congress of Biochemistry andMolecular Biology 2007 (第30回日本分子生物学会年会・第80回日本生化学会合同大会)
    • Place of Presentation
      横浜, 日本
    • Year and Date
      2007-12-13
    • Related Report
      2008 Final Research Report
  • [Presentation] KL-6 mucin as a diagnostic marker for cholangiocarcinoma2007

    • Author(s)
      Inagaki Y, Xu HL, Tang W, Nakata M, Sugawara Y, Kokudo N
    • Organizer
      China-Japan Joint Medical Workshop on Drug Discoveries and Therapeutics
    • Place of Presentation
      中国山東省済南
    • Year and Date
      2007-05-26
    • Related Report
      2007 Annual Research Report
  • [Presentation] KL-6 mucin as adiagnostic marker forcholangiocarcinoma.2007

    • Author(s)
      Inagaki Y, Xu HL, Tang W, Nakata M, Sugawara Y, Kokudo N
    • Organizer
      China-JapanJoint Medical Workshop on Drug Discoveries and Therapeuticss
    • Place of Presentation
      Jinan, China
    • Related Report
      2008 Final Research Report

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Published: 2007-04-01   Modified: 2016-04-21  

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