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Delivery of peptide-mimetic drugs to tumors utilizing oligopeptide transporters

Research Project

Project/Area Number 12557204
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Physical pharmacy
Research InstitutionKANAZAWA UNIVERSITY

Principal Investigator

TSUJI Akira  Kanazawa University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (10019664)

Co-Investigator(Kenkyū-buntansha) SAI Yoshimichi  Kanazawa University, Graduate School, Assistant Professor, 大学院・自然科学研究科, 助手 (40262589)
TAMAI Ikumi  Kanazawa University, Pharmaceutical Sciences, Assistant Professor, 薬学部, 助教授 (20155237)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥9,700,000 (Direct Cost: ¥9,700,000)
Fiscal Year 2001: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
Keywordstransporter / oligopeptide / anti-cancer reagent / bestatine / quantitative PCR / tumor / nude mouse / drug delivery / アデノウィルス / ベスタチン / グリシルサルコシン / ヌードマウス / トラックデリバリー
Research Abstract

In the present study, we studied feasibility of drug delivery using oligopeptide transporter which expressed in some tumor cell lines. During this study period, we obtained following findings.
1. A stable cell line which over expresses human oligopeptide transporter PEPT1 was established by transfecting hPEPTl cDNA into HeLa cells. Its transport actiyity was confirmed by measuring glycylsarcosine and termed the cell line HeLa-hPEPT1.
2. Nude mice (Balb/c nu/nu mice) inoculated with HeLa-hPEPT1 bared tumor within several weeks. In these mice, I.v. injected an anti-tumor drug bestatine, and dipeptide carnosine were accumulated in the hPEPT1-expressing tumors.
3. HeLa-hPEPT1 was more sensitive to bestatine than parent HeLa cell line by in vitro MTT assay. Tiimor growth of HeLa-hPEPT1 in nude mice was strongly suppressed by oral dose of bestatine to the mice, while that of HeLa inoculated mice was not affected.
4. Messenger RNA expression levels of known oligopeptide transporters that is PEPT1 and PEPT2 were quantitatively analyzed by the real time PCR in iridivisual 25 tumbf lines. Among them ML-1, Nakajima and Caco-2 cells expressed PEPT1in high level on the other hand, PEPT2 expression was observed majority of cell lines examined. Comparing mRNA expression and transport activity profiles, we found little correlation between them. Therefore, existence ofnovel transporter that represents the uptake of peptides has been suggested.
5. Molecular cloning of CDNA of organic cation transporter OCTNs and OATPs were performed and some of which were expressed in tumor cell lines.
6. We have proved that expression of amino acid transporter LAT1 and LAT2, which play roles in tumor growth, in the blood-brain barrier.
In conclusion, detailed characterization of many kinds of transporters which expressed in tumors will provide us valuable information to establish method for tumor specific delivery of drugs.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (50 results)

All Other

All Publications (50 results)

  • [Publications] Nakanishi, T.: "Cancer cell-targeted drug delivery utilizing oligopeptide transport activity"Int. J. Cancer. 88・2. 274-280 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirohashi, T.: "Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2)"J. Pharmacol. Exp. Ther.. 292・1. 265-270 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ogihara, T.: "Structural requirement of substrates for stereoselective monocarboxylate tranaport in Caco-2 cells"Pharm. Pharmacol. Commun.. 6. 161-165 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamai, I.: "Molecular arid functional characterization of organic cation/carnitine transporter family in mice"J. Biol. Chem.. 275・51. 40064-40072 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mayatepek, E.: "Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency"Hum. Mutat.. 15.1. 118 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamai, I.: "Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family"Biochem. Biophys. Res. Commun.. 273・1. 251-260 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamai, I.: "Transporter-mediated permeation of drugs across the blood-brain barrier"J. Pharm. Sci.. 89. 1371-1388 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sai, Y.: "Selective delivery of peptide anticancer drugs via oligopeptide transporter expressed in cancer cells"Millenial World Congress of Pharmaceutical Sciences Abstracts. 61 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 辻 彰: "薬物の生体膜輸送機構解析を基盤とした体内動態制御に関する研究"薬物動態. 15. 112-135 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 辻 彰: "消化管吸収過程における薬物間相互作用"月間薬事. 42. 287-293 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 辻 彰: "薬物の血液脳関門透過性の改善"Pharm. D.. 2. 1-5 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 玉井郁巳: "小腸上皮トランスポーター群の分子機構論的解析と薬物の経口デリバリーへの応用"薬物研究の進歩. 16. 77-88 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 玉井郁巳: "トランスポーターが関与する薬物動態と病態"薬事新報. 2141. 9-15 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 玉井郁巳: "OCTNトランスポーターファミリーの組織分布・輸送の多様性"薬物動態. 15. 182-188 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toyobuku H: "Enhanced delivery of drugs to the liver by adenovirus-mediated heterologous expression of human oligopeptide transporter PEPT1"J Pharmacol Exp Ther. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Naruhashi, K: "Inprovement of multidrug resistance-associated protein 2 in intestinal secretion of grepafloxacin in rats"Antimicrob. Agents Chemother.. 46・2. 344-349 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kido Y: "Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier"J. Pharm. Pharmacol.. 53・4. 497-503 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Naruhashi K: "Active intestinal secretion of new quinolone antimicrobials and the partial contribution of P-glycoprotein"J. Pharm. Pharmacol.. 53・5. 699-709 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 玉井郁巳: "薬物トランスポーター群の遺伝子多型"薬物動態. 16・2. 127-133 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 玉井郁巳: "新・ドラックデリバリーシステム"トランスポーターとドラックデリバリーシステム""シーエムシー. 13 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakanichi, T.: "Cancer cell-targeted drug delivery utilizing oligopeptide transport activity"Int. J. Cancer. 88. 274-280 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirohashi, T.: "Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2)"J. Pharmacol. Exp. Ther.. 292. 265-270 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ogihara, T.: "Structural requirement of substrates for stereoselective monocarboxylate tranaport in Caco-2 cells"Pharm. Pharmacol. Commun.. 6. 161-165 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamai, I.: "Molecular and functional characterization of organic cation/carnitine transporter family in mice"J. Biol. Chem.. 275. 40064-40072 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mayatepek, E.: "Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency"Hum. Mutat.. 15. 118 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamai, I.: "Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family"Biochem. Biophys. Res. Commun.. 273. 251-260 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tamai, I.: "Transporter-mediated permeation of drugs across the blood-brain barrier"J. Pharm. Sci.. 89. 1371-1388 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kido, Y.: "Molecular and functionalidentification of large neutral amino acid transporter LAT1 at the blood-brain barrier using rat cultured cellsMolecular and functionalidentification of large neutral amino acid transporter LAT1 at the blood-brain barrier using rat cultured cells"J. Pharm. Pharmacol.. 53. 497-503 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Naruhashi, K.: "Involvement of multidrug resistance-associated protein 2 in intestinal secretion of grepafloxacin in rats"Antimicrob. Agents Chemother.. 46. 344-349 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Naruhashi, K.: "Acitive intestinal secretion of new quinolone antimicrobaials and the partial contribution of P-glycoprotein"J. Pharm. Pharmacol.. 53. 699-709 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toyobuku H: "Enhanced delivery of drugs to the liver by adenovirus-mediated heterologous expression of human oligopeptide transporter PEPT1"J Pharmacol Exp Ther. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Naruhashi, K: "Inprovement of multidrug resistance-associated protein 2 in intestinal secretion of grepafloxacin in rats"Antimicrob. Agents Chemother.. 46・2. 344-349 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kido Y: "Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier"J. Pharm. Pharmacol.. 53・4. 497-503 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Naruhashi K: "Active intestinal secretion of new quinolone antimicrobials and the partial contribution of P-glycoprotein"J.Pharm. Pharmacol.. 53・5. 699-709 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 玉井郁巳: "薬物トランスポーター群の遺伝子多型"薬物動態. 16・2. 127-133 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakanishi,T.: "Cancer cell-targeted drug delivery utilizing oligopeptide transport activity"Int.J.Cancer. 88・2. 274-280 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hirohashi,T.: "Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2)"J.Pharmacol.Exp.Ther.. 292・1. 265-270 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ogihara,T.: "Structural requirement of substrates for stereoselective monocarboxylate tranaport in Caco-2 cells"Pharm.Pharmacol.Commun.. 6. 161-165 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tamai,I.: "Molecular and functional characterization of organic cation/carnitine transporter family in mice"J.Biol.Chem.. 275・51. 40064-40072 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mayatepek,E.: "Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency"Hum.Mutat.. 15・1. 118 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tamai,I.: "Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family"Biochem.Biophys.Res.Commun.. 273・1. 251-260 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tamai,I.: "Transporter-mediated permeation of drugs across the blood-brain barrier"J.Pharm.Sci.. 89. 1371-1388 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sai.Y.: "Selective delivery of peptide anticancer drugs via oligopeptide transporter expressed in cancer cells"Millenial World Congress of Pharmaceutical Sciences Abstracts. 61 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 辻彰: "薬物の生体膜輸送機構解析を基盤とした体内動態制御に関する研究"薬物動態. 15. 112-135 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 辻彰: "消化管吸収過程における薬物間相互作用"月刊薬事. 42. 287-293 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 辻彰: "薬物の血液脳関門透過性の改善"Pharm.D.. 2. 1-5 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 玉井郁巳: "小腸上皮トランスポーター群の分子機構論的解析と薬物の経ロデリバリーへの応用"薬学研究の進歩. 16. 77-88 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 玉井郁巳: "トランスポーターが関与する薬物動態と病態"薬事新報. 2141. 9-15 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 玉井郁巳: "OCTNトランスポーターファミリーの組織分布・輸送の多様性"薬物動態. 15. 182-188 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 玉井郁巳: "新・ドラックデリバリーシステム"トランスポーターとドラックデリバリーシステム""シーエムシー. 13 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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