Tailor-made therapy based on pharmacogenomic strategy for refractory leukemia due to multifactorial drug resistance

• Project/Area Number: 19591102
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Fukui
• Principal Investigator: UEDA Takanori University of Fukui, 医学部, 教授 (40160171)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Akira 福井大学, 医学部附属病院, 講師 (80252005) ; YAMAUCHI Takahiro 福井大学, 医学部, 講師 (90291377) ; KISHI Shinji 福井大学, 医学部, 助教 (30334816)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 白血病 / 薬剤耐性 / ゲノム薬理学 / テーラーメイド治療 / シタラビン / イダルビシン / GSTM1 / 癌 / 内科 / 薬学 / Glutathione S-trans ferase μ / Bcl-2 / ara-CTP / 5'-nucleotidase II / P2RY5 / temozolomide / 薬剤反応性 / 薬理学 / 薬物動態的自己増強

Research Abstract

しばしばmultifactorialな薬剤耐性により難治性である白血病の克服につき、抗がん薬,白血病細胞,宿主(ヒト)3者の相互関係の面から検討した。その結果Temozolomideによる他のアルキル化薬の耐性克服効果、GST-M1によるリンパ性白血病ステロイド耐性のdual mechamism,シタラビンの効果予測の酵素学的指標,イダルビシンにおけるpharmacokinetic self-potentiationなどの興味ある知見を明らかにした。

Research Products

• [Journal Article] Glutathione S-transferase M1 inhibits dexamethasone-induced apoptosis in association with the suppression of Bim through dual mechanisms in a lymphoblastic leukemia cell line (2010)
  • Author(s): N. Hosono, S. Kishi, S. Iho, Y. Urasaki, A. Yoshida, H. Kurooka, Y. Yokota, T. Ueda
  • Journal Title: Cancer Sci 101 Pages: 767-773
  • NAID: 10026589943
  • Peer Reviewed
• [Journal Article] A new high-performance liquid chromatography method determines low production of 9-β-D-arabinofuranosylguanine triphosphate, an active metabolite of nelarabine, in adult T-cell leukemia cells (2010)
  • Author(s): T. Yamauchi, R. Nishi, K. Kitazumi, T. Nakano, T. Ueda
  • Journal Title: Oncology Rep 23 Pages: 499-504
  • Peer Reviewed
• [Journal Article] Glutathione S-transferase M1 inhibits dexamethasone-induced apoptosis in association with the suppression of Bim through dual mechanisms in a lymphoblastic leukemia cell line (2010)
  • Author(s): N.Hosono, S.Kishi, S.Iho, Y.Urasaki, A.Yoshida, H.Kurooka, Y.Yokota, T.Ueda
  • Journal Title: Cancer Sci 101(3) Pages: 767-773
  • NAID: 10026589943
  • Peer Reviewed
• [Journal Article] A new high-performance liquid chromatography method determines low production of 9-β-D-arabinofuranosylguanine triphosphate, an active metabolite of nelarabine, in adult T-cell leukemia cells (2010)
  • Author(s): T.Yamauchi, R.Nishi, K.Kitazumi, T.Nakano, T.Ueda
  • Journal Title: Oncology Reports 23 Pages: 499-504
  • Peer Reviewed
• [Journal Article] Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5'-nucleotidaseIIexpression ratio in primary acute myeloid leukemia cells (2009)
  • Author(s): T. Yamauchi, E. Negoro, S. Kishi, K. Takagi, A. Yoshida, Y. Urasaki, H. Iwasaki, T. Ueda
  • Journal Title: Biochem Pharmacol 77 Pages: 1780-1786
  • Peer Reviewed
• [Journal Article] Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5'-nucleotidase II expression ratio in primary acute myeloid leukemia cells (2009)
  • Author(s): T.Yamauchi, E.Negoro, S.Kishi, K.Takagi, A.Yoshida, Y.Urasaki, H.Iwasaki, T.Ueda
  • Journal Title: Biochemical Pharmacology 77 Pages: 1780-1786
  • Peer Reviewed
• [Journal Article] Carmustine-resistant cancer cells are sensitized to temozolomide due to enhanced mismatch repair during the development of carmustine resistance (2008)
  • Author(s): T. Yamauchi, M. Ogawa, T. Ueda
  • Journal Title: Mol Pharmacol 74 Pages: 84-91
  • Peer Reviewed
• [Journal Article] Multiple inflammatory cytokine-productive ThyL-6 cell line established from a patient with thymic carcinoma (2008)
  • Author(s): K. Inai, K. Takagi, N. Takimoto, H. Okada, Y. Imamura, T. Ueda, H. Naiki, S. Noriki
  • Journal Title: Cancer Sci 99 Pages: 1778-1784
  • NAID: 10024010898
  • Peer Reviewed
• [Journal Article] Binding of monosodium urate crystals with idiotype protein efficiently promote dendritic cells to induce cytotoxic T cells (2008)
  • Author(s): I. Sakamaki, K. Inai, Y. Tsutani, T. Ueda, H. Tsutani
  • Journal Title: Cancer Sci 99 Pages: 2268-2273
  • NAID: 10024013362
  • Peer Reviewed
• [Journal Article] Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib, and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification (2008)
  • Author(s): K. Morinaga, T. Yamauchi, S. Kimura, T. Mae kawa, T. Ueda
  • Journal Title: Int J Cancer 122 Pages: 2621-2627
  • Peer Reviewed
• [Journal Article] Carmustine-resistant cancer cells are sensitized to teraozolo mide due to enhanced mismatch repair during the development of carraustine resistance. (2008)
  • Author(s): T. Yamauchi, M. Ogawa, T. Ueda
  • Journal Title: Mol Pharmacol 74 Pages: 84-91
  • Peer Reviewed
• [Journal Article] Multiple inflammatory cytokine-productive ThyL-6 cell line established from a patient with thymic carcinoma (2008)
  • Author(s): K. Inai, K. Takagi, N. Takimoto, H. Okada, Y. Imamura, T. Ueda, H. Naiki, S. Noriki
  • Journal Title: Cancer Sci 99(9) Pages: 1778-1784
  • NAID: 10024010898
  • Peer Reviewed
• [Journal Article] Binding of monosodium urate crystals with idiotype protein efficiently promote dendritic cells to induce cytotoxic T cells. (2008)
  • Author(s): I. Sakamaki, K. Inai, Y. Tsutani, T. Ueda, H. Tsutani
  • Journal Title: Cancer Sci 99 (11) Pages: 2268-2273
  • NAID: 10024013362
  • Peer Reviewed
• [Journal Article] Overcoming imatinib resistance using Src inhibitor CGP76030, Ablinhibitor nilotinib, and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification (2008)
  • Author(s): K. Morinaga, T. Yamauchi, S. Kimura, T. Maekawa, T. Ueda
  • Journal Title: Int J Cancer 122 Pages: 2621-2627
  • Peer Reviewed
• [Journal Article] 自己末梢血幹細胞移植術後に微小残存病変が定性的PCR法で陰性化した形質細胞白血病 (2008)
  • Author(s): 細野 奈穂子, 山内 高弘, 中村 徹, 山下 太郎, 上田 孝典
  • Journal Title: 癌と化学療法誌 35 Pages: 533-537
  • Peer Reviewed
• [Journal Article] Combined low-dose cytarabine, melphalan and mitoxantrone for older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome (2007)
  • Author(s): T. Yamauchi, E. Negoro, H. Arai, S. Ikegaya, K. Takagi, H. Takemura, K. Inai, A. Yoshid a, Y. Urasaki, H. Iwasaki, T. Ueda
  • Journal Title: Anticancer Res 27 Pages: 2635-2639
  • Peer Reviewed
• [Journal Article] Combined low-dose cytarabine, melphalan and mitoxantrone for older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome (2007)
  • Author(s): T. Ymauchi, E. Negoro, H. Arai, S. Ikegaya, K. Takagi, H. Takemura, K. Inai, A. Yoshida, Y. Urasaki, H. Iwasaki, T. Ueda
  • Journal Title: Anticancer Res 27 Pages: 2635-2639
  • Peer Reviewed
• [Journal Article] Ancestry and phamacogenetics of antileukemic drug toxicity (2007)
  • Author(s): S. kishi, Cheng C, French D, Pei D, Das S, Cook EH, Hijiya N, Rizzari C, Rosner GL, Frudakis T, Pui CH, Evans WE, Relling WE
  • Journal Title: Blood 15 Pages: 4151-4157
  • Peer Reviewed
• [Journal Article] Primary central nervous system lymphoma secretes monocyte chemoattractant protein 1 (2007)
  • Author(s): R. Kitai, K. Ishisaka, K. Sato, T. Sakuma, T. Yamauchi, Y. Imamura, H. Matsumoto, T. Kubota, T. Ueda
  • Journal Title: Med Mol Morphol 40 Pages: 18-22
  • NAID: 10024379375
  • Peer Reviewed
• [Journal Article] Genomic TDMに基づく白血病治療のテーラーメイド化 (2007)
  • Author(s): 山内 高弘, 上田 孝典
  • Journal Title: 月刊薬事 49 Pages: 1365-1371
• [Journal Article] 多剤併用化学療法と大量療法、造血器腫瘍-基礎・臨床領域における最新の研究動向 (2007)
  • Author(s): 山内 高弘, 上田 孝典
  • Journal Title: 日本臨床 増刊 76 Pages: 369-374
• [Presentation] 白血病細胞株におけるP2RY5遺伝子発現によるglucocorticoid感受性の検討 (2008)
  • Author(s): 細野奈緒子、岸慎治、伊保澄子、浦崎芳正、上田孝典
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-10-11
• [Presentation] Characterization of resistance to cytosine arabinoside (Ara-C) in leukemia cells with five different cell lineage (2008)
  • Author(s): E. Negoro, Y. Urasaki, T. Yamauchi, T. Ueda
  • Organizer: The 99th AACR Annual Meeting
  • Place of Presentation: San Diego, U.S. A
  • Year and Date: 2008-04-14
• [Presentation] 新規プリンヌクレオシドアナログ9-β-D-arabinofuranosylguanineの成人T細胞白血病に対する抗腫瘍効果 (2008)
  • Author(s): 山内 高弘, 西 理恵, 上田 孝典
  • Organizer: 第41回日本痛風核酸代謝学会総会
  • Place of Presentation: 福井市
  • Year and Date: 2008-02-14
• [Presentation] Unique resistance mechanism to dexamethasone by Glutathione S-transferase M1 involving p38 MAPK and NF-kB pathways, possible prognostic role for childhood ALL (2007)
  • Author(s): N. Hosono, S. Kishi, S. Iho, Y. Urasaki, A. Y oshida, H. Kurooka, Y. Yokota, T. Ueda
  • Organizer: The 49th ASH Annual Meeting
  • Place of Presentation: Atlanta, U.S.A.
  • Year and Date: 2007-12-08
• [Presentation] Unique resistance mechanism to dexamethasone by Glutathione S-transferase Ml involving p38 MAPK and NF-kB pathways, possible Prognostic role for childhood ALL (2007)
  • Author(s): N. Hosono, S. Kishi, S. Iho, Y. Urasaki, A. Yoshida, H. Kurooka, Y. Yokota, T. Ueda
  • Organizer: The 49th ASH Annual Meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-08
• [Presentation] 白血病細胞株における解毒酵素GSTM1の発現による抗腫瘍効果の検討 (2007)
  • Author(s): 細野 菜穂子, 岸 慎治, 浦崎 芳正, 吉田 明, 上田 孝典, 伊保 澄子
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-12
• [Presentation] 原発性アミロイドーシスに対するメルファラン大量療法を中心とした治療開発 (2007)
  • Author(s): 河合 泰一, 酒巻 一平, 根来 英樹, 大槻 希美, 木下 圭一, 岸 慎治, 山内 高弘, 浦崎 芳正, 吉田 明, 岩崎 博道, 津谷 寛, 上田 孝典
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-12
• [Presentation] ゲムツズマブオゾガマイシン耐性白血病細胞株の樹立と耐性機序、感受性の検討 (2007)
  • Author(s): 山内 高弘, 細野 奈穂子, 武村 晴行, 上田 孝典
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-12
• [Presentation] AP endonuclease-1によるカンプトテシン感受性増強 (2007)
  • Author(s): 浦崎 芳正, 根来 英樹, 岸 慎治, 細野 奈穂子, 上田 孝典
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-12
• [Presentation] 造血器悪性腫瘍細胞株におけるAra-C耐性機序の網羅的解析 (2007)
  • Author(s): 根来 英樹, 浦崎 芳正, 岸 慎治, 山内 高弘, 河合 泰一, 吉田 明, 岩崎 博道, 上田 孝典
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-12
• [Presentation] Cytarabine sensitivity of leukemic cells determined by the intracellular pharmacokinetics (2007)
  • Author(s): 山内高弘, 上田孝典
  • Organizer: 第66回日本癌学会総会
  • Place of Presentation: 横浜市
  • Year and Date: 2007-10-04
• [Presentation] リツキサンが末梢神経障害に有効であった原発性マクログロブリン血症 (2007)
  • Author(s): 浦崎 芳正, 根来 英樹, 田居 克規, 岸 愼治, 山内 高弘, 上田 孝典, 山村 修
  • Organizer: 第203回日本内科学会北陸地方会
  • Place of Presentation: 金沢市
  • Year and Date: 2007-09-09
• [Presentation] 新規DNAアルキル化剤Ecteinascidin-743は腫瘍細胞における転写共役ヌクレオチド除去修復を特異的に阻害する (2007)
  • Author(s): 高木 和貴, Olivier Sordet, Yves Pommier, 上田 孝典
  • Organizer: 第48回福井癌研究会
  • Place of Presentation: 福井市
  • Year and Date: 2007-06-22
• [Presentation] 原発性アミロイドーシスに対するメルファラン大量療法 (2007)
  • Author(s): 河合 泰一, 酒巻 一平, 根来 英樹, 大槻 希美, 浦崎 芳正, 岩崎 博道, 山内 高弘, 津谷 寛, 上田 孝典
  • Organizer: 第55回日本輸血・細胞治療学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2007-06-02
• [Book] 悪性リンパ腫治療マニュアル(改訂第3版) (2009)
  • Author(s): 上田孝典、南江堂
• [Book] 入門腫瘍内科学 (2009)
  • Author(s): 上田孝典
  • Publisher: 篠原出版新社
• [Book] 造血器腫瘍アトラス-形態、免疫、染色体と遺伝子- (2009)
  • Author(s): 上田孝典
  • Publisher: 日本医事新版社
• [Book] 白血病治療マニュアル改訂第3版 (2009)
  • Author(s): 上田孝典
  • Publisher: 南江堂
• [Book] 白血病治療マニュアル 改訂 第3版 (2009)
  • Author(s): 上田孝典(分担)
  • Total Pages: 326
  • Publisher: 南江堂
• [Book] わかりやすい内科学(第3版) (2008)
  • Author(s): 上田孝典
  • Publisher: 文光堂
• [Book] わかりやすい内科学(第3版) (2008)
  • Author(s): 上田 孝典
  • Total Pages: 7
  • Publisher: 文光堂
• [Book] インフォームドコンセントのための図説シリーズ 白血病 改訂版 (2007)
  • Author(s): 上田 孝典
  • Total Pages: 6
  • Publisher: 医薬ジャーナル社