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Development of methodology to study in vivo changes in polyamines levels and its application

Research Project

Project/Area Number 13672261
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Physical pharmacy
Research InstitutionJosai University

Principal Investigator

SAMEJIMA Keijiro  Josai University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00072413)

Co-Investigator(Kenkyū-buntansha) NIITSU Masaru  Josai University, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助教授 (00077976)
GODA Hitomi  Josai University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (30170690)
Project Period (FY) 2001 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
Keywordspolyamine / spermidine synthase / inhibitor / IS-MS / regenerating liver / PCNA / stable isotope / trans-4-methylcyclohexylamine / trans-4-methylcyclohexylamine / マススペクトロメトリー / 体内動態 / 癌 / イオンスプレーイオン化 / 質量分析 / トレーサー実験 / ホモロジーモデリング / ジアセチルスペルミン
Research Abstract

The purpose of this study was to examine the influence of in vivo inhibition of spermidine synthase(spd-syn) on the growth of rat tissues. This was because in vitro inhibition of spd-syn causes a similar change in spermidine(spd) and spermine(spm) levels to that observed whenever cell growth is arrested. First, the method of polyamine determination by ionspray ionization mass spectrometry was semi-automated to treat many samples, by developing the polyamine tracer method using ^<15>N-labeled polyamines and the method for determining N^1,N^<12>-diacetylspermine in the urine of cancer patients. Second, analogs of n-butylamine and trans-4-methylcyclohexylamine (4MCHA), which are potent competitive inhibitors at the putrescine binding site of spd-syn, were prepared and their inhibitory activities tested. This revealed that 5-amino-1-pentene(APE) and 4MCHA had the lowest IC_<50> value. In parallel with this research, the structure of the putrescine binding site was investigated. A possible … More three-dimensional structure of mammalian spd-syn, constructed with homology modeling and identification of the cysteine residues, showed the difficulty of designing an inhibitor from the active site structure. Third, APE and 4MCHA were administered orally to rats (once daily for 1 week), and 4MCHA alone showed a decrease in spd combined with a moderate increase in spm in rat tissues. The changes in spd and spm levels were dose-dependent, and the body-weight gain of the rats tended to decrease with increasing doses of 4MCHA. The altered polyamine levels were maintained during the extended 1-month period, with growth-dependent alteration. The results show it is possible to produce experimental rats with a higher spm:spd ratio than control rats to investigate the physiological significance of spd downregulation and spm upregulation in vivo. As an application, liver regeneration was compared between the model rats and control rats. The results showed that the inhibition of spd-syn repressed proliferation of the regenerating liver. Studies are now in progress. Less

Report

(5 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (19 results)

All 2005 2004 2003 2002 Other

All Journal Article (14 results) Publications (5 results)

  • [Journal Article] Control of Spermidine and Spermine Levels in Rat Tissues by trans-4-Methylcyclohexylamine, a Spermidine-Synthase Inhibitor2005

    • Author(s)
      Kobayashi, M. et al.
    • Journal Title

      Biol.Pharm.Bull. 28(4)

      Pages: 569-573

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Control of Spermidine and Spermine Levels in Rat Tissues by trans-4-Methylcyclohexylamine, a Spermidine-Synthase Inhibitor.2005

    • Author(s)
      M.Kobayashi, T.Watanabe, Y.J.Xu, M.Tatemori, H.Goda, M.Niitsu, A.Shirahata, K.Samejima
    • Journal Title

      Biol.Pharm.Bull. 28(4)

      Pages: 569-573

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Control of spermidine and spermine levels in rat tissues by trans-4-methylcyclohexylamine, a spermidine-synthase inhibitor2005

    • Author(s)
      N.Kobayashi, T.Watanabe, et al.
    • Journal Title

      Biol.Pharm.Bull. 28(4)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mammalian Spermidine Synthase -Identification of Cysteine Residues and Investigation of the Put Binding Site-2004

    • Author(s)
      Goda, H. et al.
    • Journal Title

      Biol.Pharm.Bull. 27(9)

      Pages: 1327-1332

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mammalian Spermidine Synthase-Identification of Cysteine Residues and Investigation of the Putrescine Binding Site-2004

    • Author(s)
      H.Goda, T.Watanabe, N.Takeda, K.Kobayashi, M.Wada, H.Hosoda, A.Shirahata, K.Samejima
    • Journal Title

      Biol.Pharm.Bull. 27(9)

      Pages: 1327-1332

    • NAID

      110003608971

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mammalian Spermidine Synthase-Identification of Cysteine Residues and Investigation of the Putrescine Binding Site-2004

    • Author(s)
      H.Goda, T.Watanabe, et al.
    • Journal Title

      Biol.Pharm.Bull. 27(9)

      Pages: 1327-1332

    • NAID

      110003608971

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Fate of Orally Administered ^<15>N-Labeled Polyamines in Rats Bearing Solid Tumors2003

    • Author(s)
      Kobayashi, M. et al.
    • Journal Title

      Biol.Pharm.Bull. 26(3)

      Pages: 285-288

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Decarboxylated S-Adenosyl-L-methionine as a Substrate for Aminopropyl Transferases2003

    • Author(s)
      Dejima, H. et al.
    • Journal Title

      Biol.Pharm.Bull. 26(7)

      Pages: 1005-1008

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Fate of Orally Administered ^<15>N-Labeled Polyamines in Rats Bearing Solid Tumors.2003

    • Author(s)
      M.Kobayashi, Y.J.Xu, K.Samejima, H.Goda, M.Niitsu, M.Takahashi, Y.Hashimoto
    • Journal Title

      Biol.Pharm.Bull. 26(3)

      Pages: 285-288

    • NAID

      110004639235

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Synthetic Decarboxylated S-Adenosyl-L-methionine as a Substrate for Aminopropyl Transferases.2003

    • Author(s)
      H.Dejima, M.Kobayashi, H.Takasaki, N.Takeda, A.Shirahata, K.Samejima
    • Journal Title

      Biol.Pharm.Bull. 26(7)

      Pages: 1005-1008

    • NAID

      110004639236

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Simultaneous Determination of Endogenous and Orally Administered ^<15>N-Labeled Polyamines in Rat Organs2002

    • Author(s)
      Xu, Y.J.et al.
    • Journal Title

      Anal.Biochem. 301(2)

      Pages: 255-260

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mass Spectrometric Separation and Determination of N^1,N^<12>-Diacetylspermine in Cancer Patients2002

    • Author(s)
      Kobayashi, M. et al.
    • Journal Title

      Biol.Pharm.Bull. 25(3)

      Pages: 372-374

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Simultaneous Determination of Endogenous and Orally Administered ^<15>N-labeled polyamines in rat organs.2002

    • Author(s)
      Y.J.Xu, T.Kara, K.Samejima, H.Sasaki, M.Kobayashi, A.Takahashi, M.Niitsu
    • Journal Title

      Anal.Biochem. 301(2)

      Pages: 255-260

    • NAID

      110004622953

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mass Spectrometric Separation and Determination of N^1,N^<12>-Diacetylspermine in Cancer Patients.2002

    • Author(s)
      M.Kobayashi, K.Samejima, K.Hiramatsu, M.Kawakita
    • Journal Title

      Biol.Pharm.Bull. 25(3)

      Pages: 372-374

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Masaki Kobayashi et al.: "Fate of Orally Administered ^<15>N-Labeled Polyamines in Rats Bearing Solid Tumors"Biol.Pharm.Bull.. 26(3). 285-288 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hideki Dejima et al.: "Synthetic Decarboxylated S-Adenosyl-L-methionine as a Substrate for Aminopropyl Transferases"Biol.Pharm.Bull.. 26(7). 1005-1008 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Masaki Kobayashi et al.: "Fate of orally administered ^<15>N-labeled polyamines in rats bearing solid tumors"Biol. Pharm. Bull.. 26. (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yong Ji Xu et al.: "Simultaneous Determination of Endogenous and Orally Administered ^<15>N-Labeled Polyamines in Rat Organs"Anal. Biochem.. 301・2. (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masaki Kobayashi et al.: "Mass Spectrometric Separation and Determination of N^1, N^<12>-Diacetylspermine in the Urine of Cancer Patients"Biol. Pharm. Bull.. 25・3. (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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