Molecular mechanisms of the antineoplastic agents inhibiting DNA replication and their applications to cancer patient treatmen

2008 Fiscal Year Final Research Report

• Project/Area Number: 19591274
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Department of Clinical Research, National Hospital Organization National Kyushu Cancer Center
• Principal Investigator: OKAMURA Jun Department of Clinical Research, National Hospital Organization National Kyushu Cancer Center, 臨床研究部, 臨床研究部長 (40360854)
• Co-Investigator(Kenkyū-buntansha): ODA Shinya 独立行政法人国立病院機構九州がんセンター, 臨床研究部・腫瘍遺伝学研究室, 室長 (40333372) ; KURAOKA Isao 独立行政法人国立病院機構九州がんセンター, 臨床研究部・腫瘍生化学研究室, 室長 (60335396) ; TAKIGUCHI Souichi 独立行政法人国立病院機構九州がんセンター, 臨床研究部・癌分子治療研究室, 研究員 (00280793) ; TAGUCHI Kenichi 独立行政法人国立病院機構九州がんセンター, 臨床研究部・腫瘍病理学研究室, 研究員 (40325527) ; YAMANAKA Takeharu 独立行政法人国立病院機構九州がんセンター, 臨床研究部・腫瘍統計学研究室, 研究員 (00325466)
• Project Period (FY): 2007 – 2008
• Keywords: DNA複製 / 抗癌剤 / 代謝拮抗剤 / 塩基アナログ / chain terminator / DNAポリメラーゼ

Research Abstract

本研究は、メソトレキセート(MTX)、6-MP、Ara-Cといった抗癌剤がDNA複製を障害する分子メカニズムを明らかにし、この過程を修飾する諸因子を明らかにすることで、これら因子群を薬剤感受性バイオマーカーとして開発することを目的とした。Ara-C、6-MPなどの塩基アナログ、およびMTXなどの葉酸拮抗剤が、DNA合成においてDNAポリメラーゼがヌクレオチドを取り込む反応を阻害する具体的な分子メカニズムを明らかにするために、ヒト細胞において主にDNA複製を担うDNAポリメラーゼのひとつ、pol delta複合体の精製をおこなった。また、このような精製標品や細胞粗抽出液を用いて、DNA複製反応におけるこれら抗癌剤の効果を観察するために、2本鎖環状DNA(プラスミド)基質を用いたgap-fillingアッセイ系を構築した。さらに、ヌクレオチド・プール不均衡がどのようにDNA複製を修飾するのか、5-FUによりもたらされるヌクレオチド・プール不均衡をモデルとして、基礎的検討を行うことを計画した。ヌクレオチド・プール不均衡は、チミジル酸合成酵素遺伝子発現の多寡によって修飾される。チミジル酸合成酵素遺伝子発現レベルを薬剤によって調節可能な細胞株が樹立されたため、この系を用いて、今後詳細な観察を行う。

Research Products

• [Journal Article] Impaired Tax-specific T-cell responses with insufficient control of HTLV-1 in a subgroup of individuals at asymptomatic and smoldering stages (2009)
  • Author(s): Shimizu Y, Takamori A, Utsunomiya A, Kurimura M, Yamano Y, Hishizawa M, Hasegawa A, Kondo F, Kurihara K, Harashima N, Watanabe T, Okamura J, Masuda T, Kannagi M
  • Journal Title: Cancer Sci 100 Pages: 481-489
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning for adult T-Cell leukemia/lymphoma:impact of antithymocyte globulin on clinical outcome (2008)
  • Author(s): Tanosaki R, Uike N, Utsunomiya A, Saburi Y, Masuda M, Tomonaga M, Eto T, Hidaka M, Harada M, Choi I, Yamanaka T, Kannagi M, Matsuoka M, Okamura J
  • Journal Title: Biol Blood Marrow Transplant 14 Pages: 702-708
  • Peer Reviewed
• [Journal Article] Low-dose methotrexate for the treatment of acute and chronic graft-versus-host disease in children (2008)
  • Author(s): Inagaki J, Nagatoshi Y, Hatanao M, Isomura N, Okamura J
  • Journal Title: Bone Marrow Transplant 41 Pages: 571-577
  • Peer Reviewed
• [Journal Article] Regulatory polymorphisms of multidrug resistance 1(MDR1) gene are associated with the development of childhood acute lymphoblastic leukemia (2007)
  • Author(s): Hattori H, Suminoe A, Wada M, Koga Y, Kohno K, Okamura J, Hara T, Matsuzaki A
  • Journal Title: Leukemia Res 31 Pages: 1633-1640
  • Peer Reviewed
• [Journal Article] Allogeneic stem cell transplantation for adult T-cell leukemia/lymphoma (2007)
  • Author(s): Okamura J, Uike N, Utsunomiya A, Tanosaki R
  • Journal Title: Int J Hematol 86 Pages: 118-125
  • Peer Reviewed
• [Presentation] Long-term survival of adult T-cell leukemia/lymphoma (ATL) by reduced-intensity stem cell transplantation (RIST) from HLA-matched sibling donors (MSD) : The Japanese ATL-RIST study (2008)
  • Author(s): Okamura J, Tanosaki R, Utsunomiya A, Uike N, Yamanaka T
  • Organizer: 33rd European Society for Medical Oncology Congress
  • Place of Presentation: Stockholm
  • Year and Date: 20080912-16
• [Presentation] Diversity in Tax specific T-cell responses among asymptomatic HTLV-I carriers (2007)
  • Author(s): Shimizu Y, Kurihara K, Takamori A, Harashima N, Utsunomiya A, Okamura J, Nishigaki K, Masuda T, Kannagi M
  • Organizer: 13th International Conference on Human Retrovirology; HTLV and Related Viruses
  • Place of Presentation: Hakone
  • Year and Date: 20070522-25
• [Presentation] Positive conversion of Tax-specific CTL response in ATL patients after hematopoietic stem cell transplantation (2007)
  • Author(s): Harashima N, Shimizu Y, Takamori A, Kurihara K, Utsunomiya A, Tanosaki R, Masuda M, Okamura J, Kannagi M
  • Organizer: 13th International Conference on Human Retrovirology; HTLV and Related Viruses
  • Place of Presentation: Hakone
  • Year and Date: 20070522-25
• [Presentation] Presence of Tax-specific cytotoxic T lymphocytes in adult T-cell leukemia patients and their functional failure (2007)
  • Author(s): Takamori A, Kurihara K, Shimizu Y, Harashima N, Choi I, Uike N, Tanosaki R, Utsunomiya A, Okamura J, Kannagi M
  • Organizer: 13th International Conference on Human Retrovirology; HTLV and Related Viruses
  • Place of Presentation: Hakone
  • Year and Date: 20070522-25
• [Presentation] Comparable Outcome of Reduced-Intensity Conditioning with or without Antithymocyte Globulin in Allogeneic Stem Cell Transplantation for Adult T-cell Leukemia:The Results of Two Prospective Studies (2007)
  • Author(s): Uike N, Utsunomiya A, Tanosaki R, Masuda M, Saburi Y, Tomonaga M, Etoh T, Kikuchi H, Harada M, Hidaka M, Choi I, Yufu Y, Matsuoka M, Kannagi M, Okamura J
  • Organizer: 13th International Conference on Human Retrovirology; HTLV and Related Viruses
  • Place of Presentation: Hakone
  • Year and Date: 20070522-25
• [Presentation] Kinetics of HTLV-1 proviral loads after allogeneic hematopoietic stem cell transplantation using reduced intensity conditioning for adult T-cell leukemia/lymphoma (2007)
  • Author(s): Utsunomiya A, Tanosaki R, Uike N, Masuda M, Saburi Y, Tomonaga M, Etoh T, Kikuchi H, Harada M, Kawano F, Choi I, Matsuoka M, Kannagi M, Sonoda S, Okamura J
  • Organizer: 13th International Conference on Human Retrovirology; HTLV and Related Viruses
  • Place of Presentation: Hakone
  • Year and Date: 20070522-25
• [Presentation] Allografting for adult T-cell leukemia/lymphoma: a nationwide retrospective analysis (2007)
  • Author(s): Hishizawa M, Kanda J, Utsunomiya A, Taniguchi T, Eto T, Moriuchi Y, Tanosaki R, Kawano F, Miyazaki Y, Nagafuji K, Hara M, Yoshiba F, Takanashi M, Kai S, Atsuta Y, Kawase T, Nagamura-Inoue T, Matsuo K,Kato S, Morishima Y, Okamura J, Kodera Y, Uchiyama T
  • Organizer: 79th American Society of hematology
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-10
• [Presentation] Treatment results of acute lymphoblastic leukemia in children; Japanese experience (2007)
  • Author(s): Okamura J
  • Organizer: 2nd Workshop of Asian Hematology
  • Place of Presentation: Bangkok
  • Year and Date: 2007-10-31
• [Book] 成人T細胞白血病/リンパ腫に対する移植. みんなに役立つ造血幹細胞移植の基礎と臨床 (2008)
  • Author(s): 崔日承、岡村純 ; 神田善伸編
  • Total Pages: 5
  • Publisher: 医薬ジャーナル社
• [Book] Oncologic emergency; 合併症と支持療法. 小児がんの診断と治療 (2007)
  • Author(s): 稲垣二郎、岡村純
  • Total Pages: 6
  • Publisher: 診断と治療社
• [Remarks]
  • URL: http://www.ia-nkcc.jp/rinsho/index.html