脳を標的とするケミカルバイオロジー:効率的に脳移行する脳腫瘍治療薬の分子デザイン

2008 Fiscal Year Annual Research Report

• Project/Area Number: 18201041
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: 石川 智久 Tokyo Institute of Technology, 大学院・生命理工学研究科, 教授 (60193281)
• Keywords: 癌 / 脳・神経 / 生理活性 / 創薬 / 分子プローブ

Research Abstract

本プロジェクト「脳を標的とするケミカルバイオロジー:効率的に脳移行する脳腫瘍治療薬の分子デザイン」において、我々は血液脳関門に発現しているABCトランスポーター(ABCB1, ABCG2等)の基質にならず、効率的に脳移行する新規脳腫瘍治療薬の分子デザインを実施する。また、これらトランスポーターを阻害する薬をデザインし、既存の制癌剤が脳腫瘍に到達できるようにする。平成20年度、我々はABCG2と相互作用する化合物をスクリーニングし、独自の定量的構造活性相関(QSAR)解析法を用いて、ABCG2の基質になる化学的構造要素を導出することに成功した。その結果に基づいて血液脳関門を通過するカンプトテシン誘導体の分子デザインをおこなった。更にABCG2を阻害する化合物をスクリーニングし、その阻害様式に基づいてABCG2を強力に阻害するプロテインキナーゼ阻害剤を見出した。脳腫瘍にはABCG2を高く発現するものがあり、ABCG2を強く阻害するプロテインキナーゼ阻害薬は、血液脳関門を効果的に通過し悪性脳腫瘍を標的とすることができる。またさらにABCG2を強く阻害するプロテインキナーゼ阻害薬は、脳腫瘍の光線力学療法の効果を向上させる可能性が新たに見つかった。ABCG2を過剰発現させた哺乳類細胞の光線感受性をプロテインキナーゼ阻害薬で高めることに成功した。(An R, et al. Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin-dependent kinase inhibitors in vitro. Pharm Res. 26 (2), 449-458, 2009.)我々の新規ABCG2阻害剤の開発が光線力学療法との補助手段として有効であろうと考えられる。

Research Products

• [Journal Article] A rapid and cost-effective SNP detection method : Application of SmartAmp2 to pharmacogenomics research (2009)
  • Author(s): Mitani Y, Lezhava A, Sakurai A, Horikawa A, Nagakura M, Hayashizaki Y, Ishikawa T.
  • Journal Title: Pharmacogenomics (印刷中)
  • Peer Reviewed
• [Journal Article] High-speed xcreening and QSAR analysis to predict durg-drug interactions of ABC transporter ABCB11 (bile salt export pump) (2009)
  • Author(s): Saito H, Hirano H, Nakamura R, Ishikawa T.
  • Journal Title: AAPS J (印刷中)
  • Peer Reviewed
• [Journal Article] Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin- dependent kinase inhibitors in vitro (2009)
  • Author(s): An R, Hagiya Y, Tamura A, Li s, Saito H, Tokushima D, Ishikawa T.
  • Journal Title: Pharmaceutical Research 26 (2) Pages: 449-458
  • Peer Reviewed
• [Journal Article] Emerging Trends in Human ABC Transporters (2009)
  • Author(s): Ishikawa T.
  • Journal Title: Pharmaceutical Research 26(2) Pages: 445-448
  • Peer Reviewed
• [Journal Article] Quality control of human ABCG2 protein in the endoplasmic reticulm : ubiquitination and proteasomal degradation (2009)
  • Author(s): Wakabayashi K, Tamura A, Furukawa T, Nakagawa H, Ishikawa T.
  • Journal Title: Advanced Drug Delivery Reviews 61 Pages: 66-72
  • Peer Reviewed
• [Journal Article] The role of human ABC transporter ABCG2 (BCRP)in pharmacotherapy (2009)
  • Author(s): Ishikawa T.
  • Journal Title: Advanced Drug Delivery Reviews 61(1) Pages: 1-2
  • Peer Reviewed
• [Journal Article] 天然物及び食品添加物による細胞内レドツクス制御機構の温故知新 (2009)
  • Author(s): 足立達彦, 萩谷祐一郎, 中川大, 石川智久
  • Journal Title: Foods & Food Ingredients Journal of Japan. 214 (1) Pages: 35-47
• [Journal Article] Nrf 2-dependent induction of human ABC transporter ABCG2 and hemeoxygenase-1 in HepG2 cells by photoactivation of porphyrins : Biochemical implications for cancer cell response to photodynamic therapy (2008)
  • Author(s): Hagiya Y, Adachi T, Ogura S, An R, Tamura A, Nakagawa H, Okura I, Mochizuki T, Ishikawa T.
  • Journal Title: Journal of Experimental Therapeutics and Oncology 7 Pages: 153-167
  • Peer Reviewed
• [Journal Article] Human ABC transporters ABCG2 (BCRP)and ABCG4 (2008)
  • Author(s): Koshiba S, An R, Saito H, Wakabayashi K, Tamura A. Ishikawa T.
  • Journal Title: Xenobiotica 38(7-8) Pages: 863-888
  • Peer Reviewed
• [Journal Article] 光毒性スクリーニングの最新手法 (2008)
  • Author(s): 田村藍, 安然, 古川朋佳, 石川智久
  • Journal Title: 谷本学校毒性質問箱 11 Pages: 152-162
• [Journal Article] ポルフィリンの光励起によるヒトABCトランスポーターABCG2とヘムオキシゲナーゼの誘導におけるNrf2の役割 (2008)
  • Author(s): 萩谷祐一郎, 足立達彦, 小倉俊一郎, 安然, 田村藍, 中川大, 望月徹, 石川智久
  • Journal Title: Porphyrins (印刷中)
  • Peer Reviewed
• [Presentation] Nrf2-dependent induction of human ABC transporter ABCG2 and hemeoxygenase-1 in HepG2 cells by photoactivation of porphyrins : Biochemical implications for cancer cell response to photodynamic therapy (2008)
  • Author(s): Hagiya Y, Adachi T, Ogura S, An R, Tamura A, Nakagawa H, Okura I, Mochizuki T, Ishikawa T.
  • Organizer: Gordon Research Conference
  • Place of Presentation: U.S.A. New Hampshire
  • Year and Date: 20080706-20080711
• [Presentation] QSAR-based identification of novel dual inhibitors against ABCG2/BCRP and protein kinases (2008)
  • Author(s): Saito H, Hirano H, Ishikawa T.
  • Organizer: Gordon Research Conference
  • Place of Presentation: U.S.A. New Hampshire
  • Year and Date: 20080706-20080711
• [Presentation] Biochemical characterization of a genetic polymorphism of human ABCC11 as a determinant of earwax type (2008)
  • Author(s): Toyoda Y, Sakurai A, Nakashima M, Nakagawa H, Yoshiura K, Niikawa N, Ishikawa T.
  • Organizer: 日本分子生物学会・日本生化学会合同大会(BMB2008)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Molecular characterization of ATP-binding cassette transporters human ABCG4 and mouse Abcg4 (2008)
  • Author(s): Koshiba S, Ishikawa T.
  • Organizer: 日本分子生物学会・日本生化学会合同大会(BMB2008)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Nrf2-dependent Induction of Humana ABC Transporter ABCG2 and Hemeoxygenase-1 in HepG2 cells by Photoactivation of Porphyrins (2008)
  • Author(s): Hagiya Y, Adachi T, Ogura S, An R, Tamura A, Nakagawa H, Okura I, Mochizuki T, Ishikawa T
  • Organizer: 日本分子生物学会・日本生化学会合同大会(BMB2008)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Expression mechanism of ABCC2 by LXR ligand T0901317 is different from that of ABCGl (2008)
  • Author(s): Adachi T, Nakagawa H, Hoshijima K, Ishikawa T.
  • Organizer: 日本分子生物学会・日本生化学会合同大会(BMB2008)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Cellular phototoxicity evoked through the inhibition of human ABC transporer ABCG2 by cyclin-dependent kinase inhibitors in vitro (2008)
  • Author(s): An R, Hagiya Y Tamura A, Li S, Saito H, Ishikawa T.
  • Organizer: 日本分子生物学会・日本生化学会合同大会(BMB2008)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] International Standardization of in vitro Assay Methods for Drug Transporters : Establishment of Transporter Working Group (2008)
  • Author(s): Ishikawa T.
  • Organizer: 日本分子生物学会・日本生化学会合同大会(BMB2008)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Cellular Phototoxicity Evoked Through the inhibition of Human ABC Transporter ABCG2 by Cyclin-dependent Kinase Inhibitors In Vitro (2008)
  • Author(s): An R, Hagiya Y, Tamura A, Li S, Saito H, Ishikawa T.
  • Organizer: 2008 桐蔭国際シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2008-10-31
• [Presentation] Biochemical characterization of a genetic polymorphism of human ABCC11 as a determinant of earwax type. (2008)
  • Author(s): Toyoda Y, Sakurai A, Nakashima M, Nakagawa H, Yoshiura K, Niikawa N,Ishikawa T.
  • Organizer: 2008 桐蔭国際シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2008-10-31
• [Presentation] Prediction of Drug-induced Intrahepatic Cholestasis : In Vitro Screening and QSAE Analysis of Drug Inhibiting the Human Bile Salt Export Pump(BSEP/ABCBn) (2008)
  • Author(s): Shin w, Saito H, Nakamura R, Sakurai A, Ishikawa T.
  • Organizer: 2008桐蔭国際シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2008-10-31
• [Presentation] Ehenic differences, functional validation and rapid detection of nonsynonymou SNP 2677G>T/A in human ABCB1 gene (2008)
  • Author(s): Sakurai A, Onishi Y Hirano H, Sakurai M, Kawai Y, Mitani Y, Lezhava A, Hayashizaki Y, Ishikawa T.
  • Organizer: 日本薬物動態学会 第23回年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] In Vitro Functional Validation of Genetic Polymorphisms of Human ATP-binding Cassette Transporter ABCB11 (SPGP/BSEP) (2008)
  • Author(s): Nakamura R. Sakurai A Ishikawa T.
  • Organizer: 日本薬物動態学会 第23回年会
  • Place of Presentation: 熊本
  • Year and Date: 2008-10-31
• [Presentation] Nrf2-dependent Induction of ABCG2 and HO-1 by Photoactivation of Porphyrins : Implications for Photodynamic Therapy (2008)
  • Author(s): Hagiya Y, Tamura A, Ishikawa T.
  • Organizer: 2008 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] In Vitro Functional Validation of Genetic Polymorphisms of Human ABCG2 : Identification of Alleles That Are Defective in Porphyrin Transport (2008)
  • Author(s): Tamura A, An R, Nakagawa H, Okura I, Ishikawa T
  • Organizer: 第8回国際ポルフィリンヘムシンポジウム
  • Place of Presentation: 島根
  • Year and Date: 2008-10-16
• [Presentation] Nrf2-dependent Induction of Human ABC Transporter ABCG2 and Heme oxygenase-1 in HepG2 cells by Photoactivation of Porphyrins : Biochemical Implications for Cancer Cell Response to Photodynamic Therapy (2008)
  • Author(s): Hagiya Y, Adachi T, Ogura S, An R, Tamura A, Nakagawa H, Okura I, Mochizuki T, Ishikawa T.
  • Organizer: 第8回国際ポルフィリンヘムシンポジウム
  • Place of Presentation: 島根
  • Year and Date: 2008-10-16
• [Presentation] Biochemical characterization of a genetic polymorphism of human ABCC11 as a determinant of earwax type. (2008)
  • Author(s): Toyoda Y, Sakurai A, Nakashima M, Nakagawa H, Yoshiura K, Niikawa N, Ishikawa T.
  • Organizer: 人類遺伝学会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-29
• [Presentation] Impact of major non・synonymous SNP(Q141K)on proteolysis of ABCG2 via lysosomal and proteasomal degradation pathways (2008)
  • Author(s): Tamura A, Wakabayashi K, An R, Furukawa T, Ishikawa T.
  • Organizer: 人類遺伝学会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-29
• [Presentation] Ethnic differences. functional validation and rapid detection of nonsynonymous SNP 2677>T/A in human ABCB1 gene (2008)
  • Author(s): Sakurai A, Onishi Y, Hirano H, Sakurai M, Kawai Y Mitani Y,Lezhava A. Hyashizaki Y. Ishikawa T.
  • Organizer: 人類遺伝学会
  • Place of Presentation: 横浜
  • Year and Date: 2008-09-29
• [Book] 小児科診療 (2009)
  • Author(s): 石川智久, 中村亮太, 侵井亜季
  • Total Pages: 123-125
  • Publisher: 株式会社診断と治療社
• [Book] バイオ医薬の開発技術とシース (2009)
  • Author(s): 斉藤光, 石川智久
  • Total Pages: 12-21
  • Publisher: シーエムシー出版
• [Book] トランスポーター研究最前線 (2008)
  • Author(s): 田村藍, 若林香菜子, 齊藤光, 石川智久
  • Total Pages: 287-303
  • Publisher: 廣川書店
• [Remarks]
  • URL: http://www.ishikawa-lab.bil.titech.ac.jp
• [Remarks]
  • URL: http://www.humanABC.bio.titech.ac.jp