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Development of a next-generation platinum-based drug with a markedly high and long-lasting antitumor efficacy

Research Project

Project/Area Number 19K07018
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
Research InstitutionSuzuka University of Medical Science

Principal Investigator

Komeda Seiji  鈴鹿医療科学大学, 薬学部, 教授 (60425056)

Co-Investigator(Kenkyū-buntansha) 平本 恵一  鈴鹿医療科学大学, 薬学部, 助教 (90251793)
古川 絢子  鈴鹿医療科学大学, 薬学部, 助教 (10455537)
植村 雅子  鈴鹿医療科学大学, 薬学部, 助教 (70511997)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsシスプラチン / 白金製剤 / DNA / 免疫 / 白金錯体 / 白金 / 金属錯体 / がん / DDS / 核酸 / 抗腫瘍効果 / EPR / プロテオミクス / アルブミン
Outline of Research at the Start

本研究は、単なる白金製剤類似化合物を合成して薬効を評価する創薬研究ではなく、構造および物理化学的性質が大きく異なる白金錯体の特性を有効利用し、大幅な薬効の向上と副作用の軽減、および作用機序の解明を目的とするものである。本研究期間中(3年)に、テトラゾラト架橋錯体の顕著な抗腫瘍効果と優れた効果持続性を裏付ける生体分子との相互作用の解明とその応用に主眼を置き、科学的根拠に基づいた応用と誘導体化を施した上で、薬効の評価・検証を行う。

Outline of Final Research Achievements

We presumed that SK36, the lead compound of tetrazolato-brdged complexes, might have an immunostimulatory effect similar to oxaliplatin, in addition to its cell-killing effect targeting DNA. We monitored antitumor efficacy by administration of oxaliplatin and SK36 on C26 colon cancer transplanted immunocompetent mice and immunodeficient mice. As a result, significant suppression of tumor growth was observed by administration of SK36 and oxaliplatin in the immunocompetent mouse group. On the other hand, administration of these drugs to immunodeficient mice did not suppress tumor-growth, and there was no significant difference in tumor volume from the control group. Therefore, it was suggested that the tumor-growth inhibition of SK36 and oxaliplatin is related to their immunostimulatory effects.The antitumor efficacy of SK36 was fouond to be much higher than oxaliplatin, confirming that the tetrazolate bridged complexes are promising candidate for next-generation platinum-based drugs.

Academic Significance and Societal Importance of the Research Achievements

本研究は、単なる白金製剤類似化合物を合成して薬効を評価するだけの創薬研究ではなく、「型破りな」白金錯体の特性を有効利用し、大幅な薬効の向上と副作用の軽減および作用機序の解明を目的とするものである。研究代表者らによる実験結果から提案された免疫賦活作用は、がん治療に極めて重要な役割を担っており、この免疫賦活作用機序の詳細を明らかにすることで、本医薬品開発研究が加速するのはもちろんのこと、免疫を利用した新たな創薬研究の発展に繋がると考えている。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (34 results)

All 2023 2022 2021 2020 2019 Other

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (22 results) (of which Int'l Joint Research: 7 results,  Invited: 4 results) Book (4 results) Remarks (3 results)

  • [Journal Article] Introduction of Fluorine into Antitumor-Active Dinuclear Platinum(II) Complexes Leads to Modulation of In Vivo Antitumor Activity in Mice2022

    • Author(s)
      Uemura M., Hiramoto K., Yoneyama H., Harusawa S., Komeda S.
    • Journal Title

      Inorganic Chemistry

      Volume: 61 Issue: 31 Pages: 12155-12164

    • DOI

      10.1021/acs.inorgchem.2c01126

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Data on synthesis and structure?activity relationships of tetrazolato-bridged dinuclear platinum(II) complexes2022

    • Author(s)
      Komeda Seiji、Yoneyama Hiroki、Uemura Masako、Tsuchiya Takahiro、Hoshiyama Miyuu、Sakazaki Tomoya、Hiramoto Keiichi、Harusawa Shinya
    • Journal Title

      Data in Brief

      Volume: 40 Pages: 107697-107708

    • DOI

      10.1016/j.dib.2021.107697

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 創薬分野における白金と白金族元素2021

    • Author(s)
      米田誠治
    • Journal Title

      金属

      Volume: 1220 Pages: 758-762

    • Related Report
      2021 Research-status Report
  • [Journal Article] Different Effects of Cisplatin and Transplatin on the Higher-Order Structure of DNA and Gene Expression2019

    • Author(s)
      Kishimoto Toshifumi、Yoshikawa Yuko、Yoshikawa Kenichi、Komeda Seiji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 1 Pages: 34-34

    • DOI

      10.3390/ijms21010034

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Associative intraligand substitution of anticancer azolato-bridged compounds without a square-pyramidal intermediate: Formation of a unique tetranuclear, μ3-1,2,3-triazolato-N1,N2,N3-bridged Pt(II) compound2019

    • Author(s)
      Komeda Seiji、In Yasuko、Tomoo Koji、Minoura Katsuhiko、Sato Takaji、Reedijk Jan、Ishida Toshimasa、Chikuma Masahiko
    • Journal Title

      Inorganica Chimica Acta

      Volume: 495 Pages: 118999-118999

    • DOI

      10.1016/j.ica.2019.118999

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] シスプラチン耐性がんに有効なアゾラト架橋白金(II)二核錯体とモノヌクレオチドの反応2023

    • Author(s)
      山田拓磨、米田誠治
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 末端アルキンを導入したテトラゾラト架橋白金(II)二核錯体の合成と細胞毒性2023

    • Author(s)
      若山実希、米山弘樹、植村雅子、宇佐美 吉英、米田 誠治
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 抗腫瘍活性を有する白金(II)二核錯体の細胞輸送におけるトランスポーターの関与2023

    • Author(s)
      植村雅子、米田誠治
    • Organizer
      日本薬学会第143年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Synthesis and characterization of tetrazolato-bridged dinuclear platinum(II) complexes with terminal alkynes2022

    • Author(s)
      若山実希、米山弘樹、植村雅子、宇佐美吉英、春沢信哉、米田誠治
    • Organizer
      第31回金属の関与する生体関連反応シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 末端アルキンを導入したテトラゾラト架橋白金(II)二核錯体の合成と細胞毒性2022

    • Author(s)
      若山実希、米山弘樹、植村雅子、宇佐美吉英、春沢信哉、米田誠治
    • Organizer
      第68回日本薬学会東海支部大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] In vitro and in vivo activity of fluoromethyl group-introduced antitumor-active dinuclear platinum(II) complex2022

    • Author(s)
      Uemura Masako、Hiramoto Keiichi、Yoneyama Hiroki、Usami Yoshihide、Harusawa Shinya、Komeda Seiji
    • Organizer
      The 8th International Symposium on Metallomics
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Tetrazolato-bridged dinuclear Pt(II) complexes and their potential applications in cancer chemotherapy2022

    • Author(s)
      Komeda Seiji、Uemura Masako、Hiramoto Keiichi
    • Organizer
      The 8th International Symposium on Metallomics
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Antitumor and immunostimulatory activities of the tetrazolato-bridged dinuclear Pt(II) complexes2022

    • Author(s)
      Komeda Seiji、Hiramoto Keiichi、Uemura Masako、Yoneyama Hiroki、Usami Yoshihide、Harusawa Shinya
    • Organizer
      10th Asian Biological Inorganic Chemistry Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] In vivo anticancer efficacy and X-ray crystal structure of the tetrazolato-bridged dinuclear Pt(II) complex2022

    • Author(s)
      Yamada Takuma、Hiramoto Keiichi、Uemura Masako、Komeda Seiji
    • Organizer
      10th Asian Biological Inorganic Chemistry Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 抗腫瘍効果を発揮するテトラゾラト架橋白金(II)二核錯体の開発研究2022

    • Author(s)
      植村雅子、米田誠治
    • Organizer
      第33回日本微量元素学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] プラチナを用いた費用対効果に優れた 制がん剤の開発2022

    • Author(s)
      米田誠治
    • Organizer
      イノベーション・ジャパン2022
    • Related Report
      2022 Annual Research Report
  • [Presentation] 抗腫瘍活性を有する白金(II)二核錯体のoxaliplatin耐性大腸がんに対するin vitro活性評価2022

    • Author(s)
      植村雅子、米田誠治
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Research-status Report
  • [Presentation] Introduction of fluorine into antitumor-active dinuclear platinum(II) complex changes in vitro/in vivo activity2021

    • Author(s)
      植村 雅子、平本 恵一、米山 弘樹、宇佐美 吉英、春沢 信哉、米田 誠治
    • Organizer
      第30回金属の関与する生体関連反応シンポジウム
    • Related Report
      2021 Research-status Report
  • [Presentation] 抗腫瘍活性を有する白金(II)二核錯体へのフッ素導入によるin vitro/in vivo活性の変化2021

    • Author(s)
      植村 雅子、平本 恵一、米山 弘樹、宇佐美 吉英、春沢 信哉、米田 誠治
    • Organizer
      日本薬学会 第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] アゾラト架橋白金(II)二核錯体によるアンドロゲン受容体を介したヒト前立腺がん細胞に対する細胞増殖抑制効果の検討2021

    • Author(s)
      新井 佑、鎌尾 まや、米田 誠治、廣田 佳久
    • Organizer
      日本薬学会 第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 「型破りな」制がん白金錯体のin vivo 抗腫瘍効果2020

    • Author(s)
      米田 誠治、植村 雅子、平本 恵一
    • Organizer
      生命金属に関する合同年会(ConMetal 2020)
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 含フッ素白金(II)二核錯体のマウス大腸がんにおける細胞内蓄積量とin vitroおよびin vivo活性評価2020

    • Author(s)
      植村 雅子、平本 恵一、米山 弘樹、宇佐美 吉英、春沢 信哉、米田 誠治
    • Organizer
      日本薬学会 第140年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Next-Generation Platinum-Based Drug2020

    • Author(s)
      Seiji Komeda
    • Organizer
      Innovation Lecture at Masaryk University supported by Ministry of Education, Youth and Sports
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 新奇なプラチナ錯体でがんは完全に治る?2019

    • Author(s)
      米田 誠治
    • Organizer
      イノベーション・ジャパン2019 ~大学見本市&ビジネスマッチング~
    • Related Report
      2019 Research-status Report
  • [Presentation] A Modification at Tetrazole C5 Markedly Influences the In Vivo Antitumor Efficacy of Tetrazolato-Bridged Dinuclear Pt(II) Complexes2019

    • Author(s)
      Seiji Komeda
    • Organizer
      15th International Symposium on Applied Bioinorganic Chemistry
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] In Vitro Cytotoxicity and In Vivo Antitumor Efficacy of Tetrazolato-Bridged Dinuclear Platinum(II) Complexes with a Bulky Substituent at Tetrazole C52019

    • Author(s)
      Masako Uemura、Keiichi Hiramoto、Hiroki Yoneyama、Shinya Harusawa、Seiji Komeda
    • Organizer
      15th International Symposium on Applied Bioinorganic Chemistry
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Development of Next-Generation Platinum-Based Drug with Markedly High and Long-Lasting Antitumor Efficacy2019

    • Author(s)
      Seiji Komeda、Masako Uemura、Keiichi Hiramoto
    • Organizer
      第29回金属の関与する生体関連反応シンポジウム
    • Related Report
      2019 Research-status Report
  • [Book] パートナー分析化学Ⅱ(改訂第4版)2021

    • Author(s)
      萩中淳、加藤くみ子
    • Total Pages
      346
    • Publisher
      南江堂
    • ISBN
      9784524403851
    • Related Report
      2021 Research-status Report
  • [Book] 生命金属ダイナミクス2021

    • Author(s)
      津本浩平、城 宜嗣
    • Total Pages
      564
    • Publisher
      (株)エヌ・ティー・エス
    • ISBN
      9784860437060
    • Related Report
      2020 Research-status Report
  • [Book] 図解 腫瘍薬学2020

    • Author(s)
      川西正祐、賀川義之、大井一弥
    • Total Pages
      677
    • Publisher
      南山堂
    • ISBN
      9784525721619
    • Related Report
      2020 Research-status Report
  • [Book] 錯体化合物事典2019

    • Author(s)
      錯体化学会
    • Total Pages
      1000
    • Publisher
      朝倉書店
    • ISBN
      9784254141054
    • Related Report
      2019 Research-status Report
  • [Remarks] Publications

    • URL

      http://www.asahi-net.or.jp/~ij4s-kmd/publications/index.html

    • Related Report
      2022 Annual Research Report
  • [Remarks] 鈴鹿医療科学大学 薬学部 機器分析学研究室

    • URL

      http://www.asahi-net.or.jp/~ij4s-kmd/publications/index.html

    • Related Report
      2021 Research-status Report
  • [Remarks] 鈴鹿医療科学大学 薬学部 機器分析学研究室

    • URL

      http://www.asahi-net.or.jp/~ij4s-kmd/index.html

    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2024-12-25  

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