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

2007 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)
• Co-Investigator(Kenkyū-buntansha): 櫻井 実 東京工業大学, バイオ研究基盤支援総合センター, 教授 (50162342) ; 土井 隆行 東京工業大学, 大学院・理工学研究科, 准教授 (90212076) ; 中川 大 東京工業大学, 大学院・生命理工学研究科, 助教 (40397039)
• 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してきた。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、制癌剤が脳腫瘍に到達できるようにするために、実験的および定量的構造活性相関解析を行った。具体的には、ABCB1の基質特異性を定量的に解析するために、50種類の化合物を用いてABCB1のATPase活性を測定し、基質認識に重要な官能基を同定した。その定量的解析の際に、我々は化合物の構造をChemical fragmentation codesで記述することにより定量的構造活性相関解析を行う独自の方法を開発した。更に一塩基多型によってABCB1の基質特異性がどのように変化するのかについても、同様の解析を行った。このような遺伝子多型に関する詳細な解析は世界初の偉業である。その研究成果は次の論文に発表されている。(Sakurai, et. al. Quantitative SAR analysis and molecular dynamic simulation to functionally validate nonsynonymous polymorphisms of human ABC transporter ABCB1. Biochemistry46(26):7678-7693,2007.)この研究成果に基づいて、遺伝子多型を持つ患者においても血液脳関門を通過して脳腫瘍をターゲットする制癌剤の分子デザインが可能になった。

Research Products

• [Journal Article] Unibiquitin-mediated proteasomal degradation of nonsynonymous SNP variants of human ABC transporter ABCG2. (2008)
  • Author(s): Nakagawa H, Tamura A, Wakabayashi K, Hoshijima K, Komada M, Yoshida T, Kometani S, Matsubara T, Mikuriya K, Ishikawa T.
  • Journal Title: Biochem. J. 411 Pages: 623-631
  • Peer Reviewed
• [Journal Article] 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, Tokushima D, and Ishikawa T.
  • Journal Title: Photochem. Photobiol. Sci (in press)
  • Peer Reviewed
• [Journal Article] Drug-induced phototoxicity evoked by inhibition of human ABC transporter ABCG2: Development of in vitro high-speed screening systems. (2008)
  • Author(s): Tamura A, An R, Hagiya Y, Hoshijima K, Yoshida T, Mikuriya K, and Ishikawa T.
  • Journal Title: Expert Opinion on Drug Metabolism and Toxicology 4(3) Pages: 255-272
  • Peer Reviewed
• [Journal Article] MRP class of human ABC transporters: Role of glutathione in the function and gene regulation. (2008)
  • Author(s): Toyoda Y, Hagiya Y, Adachi T, Hoshijima K, Kuo MT, Ishikawa T.
  • Journal Title: Xenobiotica (in press)
  • Peer Reviewed
• [Journal Article] Human ABC transporters ABCG2 (BCRP) and ABCG4. (2008)
  • Author(s): Koshiba S, An R, Saito H, Wakabayashi K, Tamura A, and Ishikawa T.
  • Journal Title: Xenobiotica, (in press)
  • Peer Reviewed
• [Journal Article] Intramolecular disulfide bond is a critical checkpoint determining degradative fates of ABC transporter ABCG2 protein. (2007)
  • Author(s): Wakabayashi K, Nakagawa H, Tamura A, Koshiba S, Hoshijima K, Komada M, and Ishikawa T.
  • Journal Title: J. Biol. Chem. 282(38) Pages: 27841-27846
  • Peer Reviewed
• [Journal Article] In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs. (2007)
  • Author(s): Tamura A, Onishi Y, An R, Koshiba S, Wakabayashi K, Hoshijima K, Priebe W, Yoshida T, Kometani, S, Matsubara T, Mikuriya K, and Ishikawa, T.
  • Journal Title: Drug Metab. Pharmacokin. 22(6) Pages: 428-440
  • Peer Reviewed
• [Journal Article] Nrf2-dependent and-independent induction of ABC transporters ABCC1,ABCC2,and ABCG2 in HepG2 cells under oxidative strees. (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Hagiya Y, Hoshijima K, Noguchi N, Kuo MT and Ishikawa, T.
  • Journal Title: J. Exp. Ther. Oncol. 6 Pages: 335-348
  • Peer Reviewed
• [Journal Article] Development of polyclonal antibodies specific to ATP-binding casstte transporters human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain. (2007)
  • Author(s): Koshiba S, Ito T, Shiota A, Wakabayashi K, Ueda M, Ichinose H, and Ishikawa T.
  • Journal Title: J. Exp. Ther. Oncol. 6 Pages: 321-333
  • Peer Reviewed
• [Journal Article] High-speed screening and quantitative SAR analysis of human ABC transporter ABCG2 for molecular modeling of anticancer drugs to circumvent multidrug resistance. (2007)
  • Author(s): Saito H, Hirano H and Ishikawa T.
  • Journal Title: Mini Rev. Medcin. Chem. 7 Pages: 1009-1018
  • Peer Reviewed
• [Journal Article] Multidrug resistance-associated protein 9 (ABCC12) is present in sperm. (2007)
  • Author(s): Ono N, van der Heiden I, Schffer GL, van de Wetering, van Deenter E, de Haas M, Boerke A, Gadella BM, de Rooij DG, Neefjes JJ, Groothuis TAM, Oomen L, Brocks L, Ishikawa T, and Borst P.
  • Journal Title: Biochem. J. 406(1) Pages: 31-40
  • Peer Reviewed
• [Journal Article] Quantitative SAR analysis and molecular dynamic simulation to functionally validate nonsynonymous polymorphisms of human ABC transporter ABCB1. (2007)
  • Author(s): Sakurai A, Onishi Y, Hirano H, Seigneuret M, Obanayama K, Kim G, Liew EL, Sakaeda T, Yoshiura K, Niikawa N, Sakurai M and Ishikawa T.
  • Journal Title: Biochemistry 46(26) Pages: 7678-7693
  • Peer Reviewed
• [Journal Article] Re-evaluation and functional classification of nonsynonymous single nucleotide polymorphisms of human ABC transporter ABCG2. (2007)
  • Author(s): Tamura A, Wakabayashi K, Onishi Y, Takeda M, Ikegami Y, Sawada S, Tsuji M, Matsuda Y and Ishikawa T.
  • Journal Title: Cancer Sci. 98(2) Pages: 231-239
  • Peer Reviewed
• [Journal Article] Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump. (2007)
  • Author(s): Sakurai A, Kurata A, Onishi Y, Hirano H and Ishikawa T.
  • Journal Title: Expert Opin. Drug Saf. 6(1) Pages: 71-86
  • Peer Reviewed
• [Journal Article] Identification of two biologically crucial hydroxyl groups of (-)-epigallocatechin gallate in osteoclast culture. (2007)
  • Author(s): Nakagawa H, Hasumi K, Takami M, Aida-Hyugaji S, Woo JT, Nagai K, Ishikawa T and Wachi M.
  • Journal Title: Biochem. Pharmacol. 73(1) Pages: 34-43
  • Peer Reviewed
• [Journal Article] Theoretical studies for molecular modeling of new camptothecin analogues. (2007)
  • Author(s): Aida-Hyugaji S, Nakagawa H, Nomura J, Sakurai M, Nagashima U and Ishikawa T.
  • Journal Title: Croatica Chemica Acta 80(2) Pages: 277-281
  • Peer Reviewed
• [Journal Article] Association of cumulative cyclosporine dose with its irreversible nephrotoxicity in Japanese patients with pediatric-onset autoimmune diseases. (2007)
  • Author(s): Nakamura T, Nozu K. Iijima K, Yoshikawa N, Moriya Y, Yamamori M, Kako A, Matsuo M, Sakurai A, Okamura N, Ishikawa T, Okumura K, Sakaeda T.
  • Journal Title: Biol. Pharm. Bull. 30(12) Pages: 2371-2375
  • Peer Reviewed
• [Presentation] Genetic Polymorphisms of ABCG2 and ER-associated Degradation (ERAD) Pathway (2008)
  • Author(s): Wakabayashi K, Tamura A, An R, Hoshijima K, Nakagawa H, Ishikawa T.
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080303-05
• [Presentation] Quantitative structure-activity relationship analysis and molecular dynamics simulation to functionally validate nonsynonymous polymorphisms of human ABCG1 (P-glycoprotein/MDR1) (2008)
  • Author(s): Sakurai A, Onishi Y, Liew Ei Leen, Hirano H, Sakurai M, Seigneuret M, Ishikawa T,
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080302-04
• [Presentation] Development of Polyclonal antibodies specific to human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain (2008)
  • Author(s): Koshiba S, Ito T, Wakabayashi K, Ichinose H, Ishikawa T.
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080302-04
• [Presentation] Identification and Inhibitory Characterization of Protein Kinase Inhibitors Based on QSAR Analysis of Human ABC Transporter ABCG2 (2008)
  • Author(s): Saito H, Hirano H, Hirono S, Tokushima D, Ishikawa T.z
  • Organizer: 2nd FEBS Special Meeting ABC2008
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20080302-04
• [Presentation] Functional Validate Nonsynonymous Polymorphisms of Human ABCB1 Transporter ABCB1 (P-glycoprotein/MDR1) (2007)
  • Author(s): Sakurai A, Onishi Y, Hirano H, Liew Ei Leen, Obanayama K, Kim G, Sakurai M Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Disulfide Bond Formation Plays a Crucial Role in Protein Stability of Human ABCG2 (2007)
  • Author(s): Wakabayashi K, Nakagawa H, Tamura A, Hoshijima K, Komada M, Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Evidence for ubiquitinqtion and degradation of non-synonymous SNP proteins of human ATP-binding cassette transporter ABCG2 (2007)
  • Author(s): Nakagawa H, Tamura A, Wakabayashi K, Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Transport Mechanism-Based Drug Molecular Design: High-Speed Screening and Quantitative SAR Analysis of ABC Transport ABCG2 to design Novel Anticancer Drugs (2007)
  • Author(s): Saito H, Hirano H, Ikegami Y, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Evaluation and Functional Classification of Nonsynonymous Single Nucleotide Polymorphisms of Human ABC Transporter ABCG2 (2007)
  • Author(s): Tamura A, Wakabayashi K, Ikegami Y, Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Critical Role of Human ABC Transporter ABCG2 in Cancer Photodynamic Therapy and Porphyria Risk (2007)
  • Author(s): An R, Tamura A, Onishi Y, Ishikawa T
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Development of polyclonal antibodies specific to ATP-binding cassette transporters human ABCG4 and mouse Abcg4: Site-specific expression of mouse Abcg4 in brain (2007)
  • Author(s): Koshiba S, Ito T, Wakabayashi K, Ichinose H, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Liver X receptor ligands include the expression of ATP-binding cassette transporter ABCG2 in human Hepatoma HepG2 cells (2007)
  • Author(s): Adachi T, Nakagawa H, Hoshijima K, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Development of Expression system of A Novel Human ATP-Binding Cassette treansporter ABCC11 (2007)
  • Author(s): Toyoda Y, Sakurai A, Yoshiura K, Miwa N, Niikawa N, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Nrf2-dependent Induction of ABCC2 and ABCG2 in HepG2 cells under Oxidative Stress (2007)
  • Author(s): Hagiya Y, Adachi T, Nakagawa H, Hoshijima K, Noguchi N, Ishikawa T.
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Characterization and Classification of CDK Inhibitors by QSAR Analysis of Human ABC Transporter ABCG2 (2007)
  • Author(s): Saito H, Hirano H, Hirono S, Tokushima D, Ishikawa T
  • Organizer: 8th International ISSX Meeting
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-10
• [Presentation] QSAR Analysis of Human ABC Transporter ABCB1 (P-GP/MDR1): Effect of SNPs on the Substrate Specificity toward CDK Inhibitors (2007)
  • Author(s): Liew Ei Leen, Sakurai A, Hirano H, Seigneuret M, Ishikawa T
  • Organizer: 8th International ISSX Meeting
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-10
• [Presentation] International Standardization of the Methods for In-vitro Funtional Analysis of Drug Transporters (2007)
  • Author(s): Ishikawa T
  • Organizer: 8th International ISSX Meeting (Short Course2)
  • Place of Presentation: 仙台
  • Year and Date: 2007-10-09
• [Presentation] Critical role of human ABC transporter ABCG2 in cancer photodynamic therapy and porphyria risk (2007)
  • Author(s): Ishikawa T, Wakabayashi K, Saito H, Sakurai A, Tamura A
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Disulfide Bond Formation Plays a Crucial Role in Protein Stability of Human ABCG2 (2007)
  • Author(s): Ishikawa T, Wakabayashi K, Saito H, Sakurai A, Tamura A
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Evaluation and Functional Classification of Nonsynonymous Single Nucleotide Polymorphisms of Human ABC Transporter ABCG2 (2007)
  • Author(s): Tamura A, Wakabayashi K, Ikegami Y, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Functionally Validate Nonsynonymous Polymorphisms of Human ABC Transporter ABCB1 (P-glycoprotein/MDR1) (2007)
  • Author(s): Sakurai A, Tamura A, Saito H, Wakabayashi K, Sakaeda T, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Expression of ABC transporter mRNA in Cololectal cancer Specimen (2007)
  • Author(s): Satake K, Ikegami Y, Sano K, Yamane Y, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] High-Speed Screening and QSAR Analysis of Human ABC Transporter ABCG2 for Molecular Modeling of Anticancer Drugs (2007)
  • Author(s): Saito H, Tamura A, Wakabayashi K, Sakurai A, Ishikawa T
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] A New Strategy of High-Speed Screening and Quantitative SAR Analysis to Evaluate Human ABC Transporter ABCG2-Drug Interactions (2007)
  • Author(s): Saito H, Hirano H, Osumi M, , Ishikawa T
  • Organizer: Gordon Research Conference on Drug Metabolism
  • Place of Presentation: NH U.S.A.
  • Year and Date: 2007-07-11
• [Presentation] Functional validation of genetic plymorphisms of ABCB1 (P-glycoprotein/MDR1): Quantative SAR analysis and moleculae dynamic simulation (2007)
  • Author(s): Sakurai A, Onishi Y, Liew Ei Leen, Hirano H, Sakurai M, Seigneuret M, Ishikawa T,
  • Organizer: Gordon Research Conference on Drug Metabolism
  • Place of Presentation: NH U.S.A.
  • Year and Date: 2007-07-11
• [Presentation] Re-evalution and functional classification of nonsynonymous single nucleotide polymorphisms of human ABC transporter ABCG2 (2007)
  • Author(s): Tamura A, Wakabayashi K, Takeda M, Ikegami Y, Ishikawa T
  • Organizer: 4th World Conference on Drug Absorption, Transport and Delivery
  • Place of Presentation: 金沢
  • Year and Date: 2007-06-21
• [Presentation] Functional validation of genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1): The funtional impact of tetra-allelic SNPs 2677G>T,A, or C (2007)
  • Author(s): Sakurai A, Onishi Y, Liew Ei Leen, Hirano H, Sakurai M, Seigneuret M, Ishikawa T,
  • Organizer: 4th World Conference on Drug Absorption, Transport and Delivery
  • Place of Presentation: 金沢
  • Year and Date: 2007-06-21
• [Presentation] Nrf2/Keap1系によって発現制御を受けるABCトランスポーターの探索 (2007)
  • Author(s): Hagiya H, et. al.
  • Organizer: 第2回トランスポーター研究会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-09
• [Presentation] ヒトABCトランスポーターABCG2のポルフィリン輸送における薬理学的役割:薬物によるABCG2の阻害と光毒性との関係 (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Kuo M.T, Ishikawa T.
  • Organizer: 第34回ポルフィリン研究会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] Development of specific antibodies against mouse ATP-binding cassette transporter Abcg4 and expression of Abcg4 in Sf9 insect cells. (2007)
  • Author(s): Koshiba S, Ito T, Ichinose H., Ishikawa, T.
  • Organizer: AACR Annual Meeting 2007
  • Place of Presentation: Los Angeles, U.S.A.
  • Year and Date: 2007-04-16
• [Presentation] Nrf2-dependent and indepenndent transcriptional upregulation of ABCC1, ABCC2, ABCC3, and ABCG2 genes in HepG2 cells. (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Kuo M.T, Ishikawa T.
  • Organizer: AACR Annual Meeting 2007
  • Place of Presentation: Los Angeles, U.S.A.
  • Year and Date: 2007-04-16
• [Presentation] ヒトABCトランスポーターABCG2のポルフィリン輸送における薬理学的役割:薬物によるABCG2の阻害と光毒性との関係 (2007)
  • Author(s): Adachi T, Nakagawa H, Chung I, Kuo M.T, Ishikawa T.
  • Organizer: 第34回ポルフィリン研究会
  • Place of Presentation: Los Angeles, U.S.A.
  • Year and Date: 2007-04-16
• [Book] トランスポーター科学最前線 (2008)
  • Author(s): 辻 彰, 田村 藍, 若林 香奈子, 齊藤 光, 石川 智久, 他28名
  • Total Pages: 374
  • Publisher: 京都 廣川書店
• [Remarks]
  • URL: http://www.ishikawa-lab.bio.titech.ac..jp
• [Remarks]
  • URL: http://www.humanABC.bio.titech.ac.jp