Fundamental Research on Hybrids of MRI Contrast Agents and Antitumor Agents to Innovate in Diagnosis and Curing Cancers Efficiently at the Very Early Stage

2011 Fiscal Year Final Research Report

• Project/Area Number: 21650108
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Biomedical engineering/Biological material science
• Research Institution: Shizuoka University
• Principal Investigator: YAMASHITA Mitsuji 静岡大学, 創造科学技術大学院, 特任教授 (60110748)
• Co-Investigator(Kenkyū-buntansha): SAKAHARA Harumi 浜松医科大学, 医学部, 教授 (10187031) ; TAKEHARA Yasuo 浜松医科大学, 医学部附属病院, 准教授 (70188217) ; NAKAMURA Satoki 浜松医科大学, 医学部附属病院, 助教 (20377740) ; OKANO Takashi 東京慈恵会医科大学, 医学部, 教授 (90194373) ; FUJIE Michio 浜松医科大学, 技術部, 技術専門員 (90397373)
• Co-Investigator(Renkei-kenkyūsha): MULLER Robert (MULLER NICOLAS Henry) University of Mons, Belgium, School of Medicine and Pharmacy, 教授(学部長) ; F. DAVID Wiemer University of Iowa, USA, Department of Medicine, 教授(学部長) ; GYORGY Keglevich Budapest University of Technology and Economics, Hungary, Dept. of Organic Chemistry and Technology, 教授(学部長) ; C. SURESH Reddy Sri Venkateswara University, India, Dept. of Chemistry, 准教授
• Project Period (FY): 2009 – 2011
• Keywords: がん早期発見 / がん早期治療 / MRI造影剤 / リン糖抗がん剤 / 複合機能化

Research Abstract

The project contained three sub-research thema(1).(3) and the progress of the research was 80% completion.(1) R & D of sugar dendritic Gd-DTAP complex for MRI contrast agents DEN-OH and the modification was 80% successful to develop novel blood pool MRI contrast agents and DEN-OH(prepared via hydrolysis route) drew clear blood vessels and liver cancers. The r1 value for DEN-OH and modified sugar Dendritic Gd-DTPA complexes were 20. 31[mmol-1・s-1], which are superior to clinically used Gd-DTPA(r1=3. 5[mmol-1・s-1]) by 10 times.(2) Phospha sugar antitumor agents were developed. Among them, TBMPP and DBMPP were most active and the analogs showed 10-1000 times more active than Gleevec(clinically used drug). TBMPP suppressed the expression of Cdc25B, which is a common factor of cell cycle for various kinds of cancer cells. Therefore, phospha sugars must most probably be developed as new"Multiple Type Molecular Targeted Antitumor Agents"and the drug may cure various types of cancer patients by the single drug.(3) The application of the results(1) and(2) provided new drugs for diagnosing and curing cancers in the sub-research thema, whose results will not be disclosed at the present stage.

Research Products

• [Journal Article] Synthesis and evaluation of novel phosphasugar anticancer agents (2012)
  • Author(s): Mayumi Yamaoka, Mitsuji Yamashita, Manabu Yamada, Michio Fujie, Keita Kiyofuji, Nobuhisa Ozaki, Kazuhide Asai, Taishi Niimi, Takuya Suyama, Junko Yamashita, Akiho Sawada, Reiko Makita, Masaki Sugiyama, MitsuoToda, Satoki Nakamura, and Kazunori Ohnishi
  • Journal Title: Pure and Applied Chemistry Volume: 84(1) Pages: 37-48
  • Peer Reviewed
• [Journal Article] Transcriptional repression of Cdc25B byIER5 inhibits the proliferation of leukemic progenitor cells through NF-YB and p300 in acute myeloid leukemia (2011)
  • Author(s): Satoki Nakamura, Yasuyuki Nagata, Lin Tan, Tomonari Takemura, Kiyoshi Shibata, Michio Fujie, Shinya Fujisawa, Yasutaka Tanaka, Mitsuo Toda, Reiko Makita, Kenji Tsunekawa, Manabu Yamada, Mayumi Yamaoka, Junko Yamashita, Kazunori Ohnishi, and Mitsuji Yamashita
  • Journal Title: PLoS One Volume: 6(11)
  • Peer Reviewed
• [Journal Article] Preparation and evaluation of novel sugar dendritic Gd-DTPA complexes for MRI contrast agents and phosphasugars for anti-tumour agents (2011)
  • Author(s): Keita Kiyofuji, Kenji Tsunekawa, Mitsuji Yamashita, Junko Yamashita, Michio Fujie, Kazuhide Asai, Takuya Suyama, Satoru Ito, Valluru Krishna Reddy, Manabu Yamada, Keisuke Ogawa, Nobuhisa Ozaki, Masaki Sugiyama, Mayumi Yamaoka, Reiko Makita, Satoki Nakamura, Takashi Aoki, Gang Yu, Kengo Aoshima, Nao Kamikage, Yasuo Takehara, Harumi Sakahara, Hisao Takayanagi, Sophie Laurent, Carmen Burtea, Luce Vander Elst, and Robert N. Muller
  • Journal Title: Advanced Materials Research Volume: 222 Pages: 217-220
  • Peer Reviewed
• [Journal Article] Preparation of phosphosugar analogs and their evaluation as novel anticancer agents (2011)
  • Author(s): Kenji Tsunekawa, Mitsuji Yamashita, Michio Fujie, Taishi Niimi, Takuya Suyama, Kazuhide Asai, SatoruIto, Junko Yamashita, Manabu Yamada, Nobuhisa Ozaki, and Satoki Nakamura
  • Journal Title: Phosphorus, Sulfur and Silicon and the Related Elements Volume: 186(4) Pages: 936-944
  • Peer Reviewed
• [Journal Article] Preparation and Characterization of Phospha Sugar Analogs, 2, 3-Dibromo-3-methyl-1-phenylphospholane 1-Oxide Derivatives, as Novel Anticancer Agents (2010)
  • Author(s): Manabu Yamada, Kazuhide Asai, Junko Yamashita, Takuya Suyama, Taishi Niimi, Kasthuraiah Maddali, Michio Fujie, Satoki Nakamura, and Mitsuji Yamashita
  • Journal Title: Phosphorus, Sulfur and Silicon and the Related Elements Volume: 185(11) Pages: 2286-2291
  • Peer Reviewed
• [Journal Article] Preparation and characterization of novel 4-bromo-3, 4-dimethyl-1-phenyl-2-phospholene 1-oxide and the analogous phosphorus heterocycles or phospha sugars (2010)
  • Author(s): Manabu Yamada, Mitsuji Yamashita, Takuya Suyama, Junko Yamashita, Kazuhide Asai, Taishi Niimi, Nobuhisa Ozaki, Michio Fujie, Kasthuraiah Maddali, Satoki Nakamura, and Kazunori Ohnishi
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 20(19) Pages: 5943-5946
  • Peer Reviewed
• [Journal Article] Development and pharmacologic characterization of deoxy bromophospha sugar derivatives with antileukemic activity (2010)
  • Author(s): Satoki Nakamura, Mitsuji Yamashita, Daisuke Yokota, Isao Hirano, Takaaki Ono, Michio Fujie, Kiyoshi Shibata, Taishi Niimi, Takuya Suyama, Kasthuraiah Maddali, Kazuhide Asai, Junko Yamashita, Yukiko Iguchi, and Kazunori Ohnishi
  • Journal Title: Investigational New Drugs Volume: 28(4) Pages: 381-391
  • Peer Reviewed
• [Journal Article] Bioorganic & Medicinal (2010)
  • Author(s): Nobuhisa Ozaki, Arigara Uma Ravi Sankar, Mitsuji Yamashita, Takashi Aoki, Yasutaka Tanaka, Motohiko Kimura, Mitsuo Toda, Michio Fujie, Yasuo Takehara, and Harumi Sakahara
  • Journal Title: Chemistry Letters Volume: 20(3) Pages: 932-934
  • Peer Reviewed
• [Journal Article] Synthesis of some 1-aryl-2, 3-dibromophospholanesas novel anti-cancer agents (2010)
  • Author(s): Manabu Yamada, Kazuhide Asai, Junko Yamashita, Takuya Suyama, Taishi Niimi, Kasthuraiah Maddali, Michio Fujie, Satoki Nakamura, Motohiko Kimura, Yasutaka Tanaka, Mitsuo Toda, and Mitsuji Yamashita
  • Journal Title: Heterocyclic Communications Volume: 16(2-3) Pages: 173-180
  • Peer Reviewed
• [Journal Article] Research and development of phospha sugar anti-cancer agents with anti-leukemic activity (2010)
  • Author(s): Junko Yamashita, Takuya Suyama, Kazuhide Asai, Manabu Yamada, Taishi Niimi, Michio Fujie, Satoki Nakamura, Kazunori Ohnishi, and Mitsuji Yamashita
  • Journal Title: Heterocyclic Communications Volume: 16(2-3) Pages: 89-97
  • Peer Reviewed
• [Presentation] Research and Development of Medicinal Materials for Diagnosing and Curing Cancer(3)-Synthesis and Evaluation of Novel Phospha Sugar Anti-cancer Agents (2011)
  • Author(s): M. Yamashita, et. al.
  • Organizer: Inter-Academia 2011
  • Place of Presentation: Alexandru Ioan Cuza University(Sucevita, Romania)
  • Year and Date: 20110900
• [Presentation] Medicinal Materials for Diagnostic Imaging and Curing Tumors : Syntheses and Evaluation of Sugar-Ball-Dendritic MRI Contrast Agents and Phospha Sugars (2011)
  • Author(s): Mitsuji Yamashita, et. al.
  • Organizer: 21st International Symposium on Glycoconjugates
  • Place of Presentation: University of Vienna(Vienna, Austria)
  • Year and Date: 20110800
• [Presentation] Preparation and Evaluation of Novel Phospha Sugars or Phospholanes for Anti-cancer Agents (2011)
  • Author(s): Mayumi Yamaoka, Mitsuji Yamashita, et al
  • Organizer: 23rd International Congress on Heterocyclic Chemistry(ICHC2011)
  • Place of Presentation: Glasgow Science Centre(Glasgow, Scotland, UK)
  • Year and Date: 20110800
• [Remarks]
  • URL: http://shizuoka-6m.web.infoseek.co.jp/yama/yama.htm
• [Patent(Industrial Property Rights)] 基材の親水化処理方法および親水性基材 (2011)
  • Inventor(s): 山下光司、小坂友護
  • Industrial Property Rights Holder: 山下光司
  • Industrial Property Number: 特許、特許登録第4703954号
  • Acquisition Date: 2011-03-18
• [Patent(Industrial Property Rights)] エポキシ誘導体の製造方法 (2009)
  • Inventor(s): 山下光司
  • Industrial Property Rights Holder: 山下光司
  • Industrial Property Number: 特許、特許登録第4417616号
  • Acquisition Date: 2009-12-04