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Identification of organic anion transporter LST-2 which expressed in the gastrointestinal cancers: clinical implication for anticancer drug delivery.

Research Project

Project/Area Number 13557218
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 応用薬理学・医療系薬学
Research InstitutionTohoku University

Principal Investigator

ABE Takaaki  Tohoku University Hospital, Lecturer, 医学部附属病院, 講師 (80292209)

Co-Investigator(Kenkyū-buntansha) HARADA Shizuko  National Institute of Infectious Diseases, Department of Virology I, Primary Investigator, ウイルス第一部, 主任研究官 (10218646)
UNNO Michiaki  Tohoku University Hospital, Lecturer, 医学部附属病院, 講師 (70282043)
YAMORI Takao  Japanease Foundation for Cancer Research, Cancer Chemotherapy Center, Molecular Pharmacology, Chairman, 癌化学療法センター・分子薬理部, 部長(研究職)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2002: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2001: ¥6,100,000 (Direct Cost: ¥6,100,000)
Keywordsorganic anion transporter / anti-cancer drug / cancer / methotrexate / hormone / 有機アニオン / トランスポーター / 感受性試験 / アデノウイルス
Research Abstract

Background & Aims: One approach to the development of targeted cancer chemotherapy exploits increased uptake of the agent into neoplastic cells. In this scenario, higher concentrations of the agent in cancer cells are responsible for differential killing while the low concentration in normal human cells decreases side effects. The aim of this study is to isolate an organic anion transporter which in weakly in normal, but abundantly expressed in cancer cells, to deliver the anti-cancer drugs to the cells.
Methods: A human liver cDNA library was screened with LST-1 cDNA as a probe, Northern blot analyses were performed using the isolated cDNA (termed LST-2). A LST-2 specific antibody was raised and immunohistochemical analyses including immuno-electron microscopy were performed. Xenopus oocyte expression system was used for functional analysis. We also established a permanent cell line which consistently expresses LST-2 to examine the relationship between MTX uptake and sensitivity.
Results: The isolated cDNA, LST-2 has 79,7 % of overall homology wish human LST-1. LST-2 exclusively expressed in the liver under normal conditions and immunoreactivity was highest at the basolateral membrane of the hepatocytes around the central vein. Although its weak expression in the liver, LST-2 is abundantly expressed in the gastric, colon and pancreatic cancers, On she other hand, she LST-1 was only detected in a hepatic cell line, LST-2 transports methotrexate in a saturable and dose dependent manner Furthermore, introduction of the LST-2 gene into mammalian cells potentiates sensitivity to methotrexate.
Conclusion: LST-2 is one of the prime candidate molecule for determining methotrexate sensitivity and may be a good target on deliver anti-cancer drugs to the gastrointestinal cancers.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Suzuki T, Onogawa T, Abe T et al.: "Identification and characterization of novel rat and human gonad specific organic anion transporters"Mol. Endocrinol.. (In press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohtsuki S, Takizawa T, Abe T et al.: "In Vitro Study of the Functional Expression of Organic Anion Transporting Polypeptide 3 at Rat Choroid Plexus Epithelial Cells and Its Involvement in the Cerebrospinal Fluid-Blood Transport of Estrone-3-Sulfate"Mol. Pharmacol.. 63. 532-537 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe T, Suzuki T, Unno M et al.: "Thyroid hormone transporters : recenrt advances"Trends in Endocrinol. Metab.. 13. 215-220 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe T, Suzuki T, Ito S et al.: "The human heaptocyte-specific organic anion transporter encoded by the SLC21A8 gene"Gastroenterology. 122. 1545-1546 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kodawara T, Masuda S, Abe T et al.: "Organic anion transporter oatp2-mediated interaction between digoxin and amiodarone in the rat liver"Pharmaceutical Res.. 19. 738-743 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shitara Y, Sugiyama D, Abe T et al.: "Comparative inhibitory effects of different compounds on rat oatp1 (slc21a1)-and Oatp2 (Slc21a5)-mediated transport"Pharmaceutical Res.. 19. 147-153 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito A, Yamaguchi K, Abe T et al.: "Distribution of Organic Anion-Transporting Polypeptide 2 (oatp2) and oatp3 in the Rat Retina"Invest. Ophthalmol. Vis. Sci.. 43. 858-863 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sasaki M, Suzuki H, Ito K, Abe T, Sugiyama Y.: "Transcellular transport of organic anions across a double-transfected Madin-Darby Canine Kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2)"J. Biol. Chem.. 277. 6497-6503 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sugiyama D., Kusuhara H, Shitara Y, Abe T, Sugiyama Y: "Effect of 17beta-Estradiol-D-17beta-Glucuronide on the Rat Organic Anion Transporting Polypeptide 2-Mediated Transport Differs Depending on Substrates"Drug Metab Dispos.. 30. 220-223 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki T, Onogawa T, Abe T et.al.: "Identification and characterization of novel rat and human gonad specific organic anion transporters"Mol. Endocrinol.. in press. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohtsuki S, Takizawa T, Abe T et.al.: "In Vitro Study of the Functional Expression of Organic Anion Transporting Polypeptide 3 at Rat Choroid Plexus Epithelial Cells and Its Involvement in the Cerebrospinal Fluid-to-Blood Transport of Estrone-3-Sulfate"Mol. Pharmacol.. Vol.63. 532-537 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe T, Suzuki T, Unno M et. Al.: "Thyroid hormone transporters: recent advances"Trends in Endocrinol. Metab.. Vol.13. 215-220 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Abe T, Suzuki T, Ito S et. Al.: "The human heaptocyte-specific organic anion transporter encoded by the SLC21A8 gene"Gastroenterology. Vol.122. 1545-1546 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kodawara T, Masuda S, Abe T et. Al.: "Organic anion transporter oatp2-mediated interaction between digoxin and amiodarone in the rat liver"Pharmaceutical Res.. Vol.19. 738-743 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shitara Y, Sugiyama D, Abe T et. Al.: "Comparative inhibitory effects of different compounds on rat oatpl (slc2la51)- and Oatp2 (Slc2la5)-mediated transport"Pharmaceutical Res.. Vol.19. 147-153 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito A, Yamaguchi K, Abe T et. Al.: "Distribution of Organic Anion-Transporting Polypeptide 2 (oatp2) and oatp3 in the Rat Retina"Invest. Ophthalmol. Vis. Sci.. Vol.43. 858-863 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sasaki M, Suzuki H, Ito K, Abe T, Sugiyama Y: "Transcellular transport of organic anions across a double-transfected Madin-Darby Canine Kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC2IA6) and multidrug resistance-associated protein 2 (MRP2/ABCC2)"J. Biol. Chem.. Vol.277. 6497-6503 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sugiyama D, Kusuhara H, Shitara Y, Abe T, Sugiyama Y: "Effect of I7beta-Estradiol-D-I7beta-Glucuronide on the Rat Organic Anion Transporting Polypeptide 2-Mediated Transport Differs Depending on Substrates"Drug Metab Dispos.. Vol.30. 220-223 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki T, Onogawa T, Abe T et al.: "Identification and characterization of novel rat and human gonad specific organic anion transporters"Mol. Endocrinol.. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohtsuki S, Takizawa T, Abe T et al.: "In Vitro Study of the Functional Expression of Organic Anion Transporting Polypeptide 3 at Rat Choroid Plexus Epithelial Cells and Its Involvement in the Cerebrospinal Fluid-to-Blood Transport of Estrone-3-Sulfate"Mol. Pharmacol.. 63. 532-537 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Abe T, Suzuki T, Unno M et al.: "Thyroid hormone transporters : recent advances"Trends in Endocrinol. Metab.. 13. 215-220 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Abe T, Suzuki T, Ito S et al.: "The Human heaptocyte-specific organic anion transporter encoded by the SLC21A8 gene"Gastroenterology. 122. 1545-1546 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kodawara T, Masuda S, Abe T et al.: "Organic anion transporter oatp2-mediated interaction between digoxin and amiodarone in the rat liver"Pharmaceutical Res.. 19. 738-743 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shitara Y, Sugiyama D, Abe T et al.: "Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)-and Oatp2 (Slc21a5)-mediated transport"Pharmaceutical Res.. 19. 147-153 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ito A, Yamaguchi K, Abe T et al.: "Distribution of Organic Anion-Transporting Polypeptide 2 (oatp2) and oatp3 in the Rat Retina"Invest. Ophthalmol. Vis. Sci.. 43. 858-863 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sasaki M, Suzuki H, Ito K, Abe T, Sugiyama Y.: "Transcellular transport of organic anions across a double-transfected Madin-Darby Canine Kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2)"J. Biol. Chem.. 277. 6497-6503 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sugiyama D.Kusuhara H, Shitara Y, Abe T, Sugiyama Y: "Effect of 17beta-Estradiol-D-17beta-Glucuronide on the Rat Organic Anion Transporting Polypeptide 2-Mediated Transport Differs Depending on Substrates"Drug Metab Dispos.. 30. 220-223 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sasaki M., Suzuki H., Ito K., Abe T., Sugiyama Y.: "Transcellular transport of organic anions across a double-transfected Madin-Darby Canine Kidney II cell monolayer expressing both human organic anion-transporting polypeptide(OATP2/SLC21A6)and multidrug resistance-associated protein 2"J Biol Chem.. 277. 6497-6503 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Abe T., Michiaki U., Tokui T., et al.: "LST-2, a human liver-specificorganic anion transporter detemines methotrexate sensitivity in the gastrointestinal cancers."Gastroenterology. 120. 1689-1699 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujiwara k., Adachi H., Nishio T., Tokui T., Okabe M., Abe T.et al.: "Isolation of a novel human organic anion transporting polypeptide OATP-E which transports thyroid hormone."Endocrinology. 142. 2005-2012 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takeuchi A., Masuda S., Saito H., Abe T.and Inui K.: "Multispecific substrate recognition of kidney-specific organic anion transporers OAT-K1 and OAT-k2."J Pharmacol Exp Ther. 299. 1-7 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sugiyama D., Kusuhara H., Shitara Y., Abe T., et al.: "Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier."J Pharmacol Exp Ther. 298. 316-322 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakai D., Nakagomi R., Furuta F., Tokui T., Abe T., Ikeda T., Nishimura K.: "Human Liver-specific Organic Anion Transporter, LST-1, Mediates Uptake of Pravastain by Human Hepatocytes."J Pharmacol Exp Ther. 295. 861-867 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 阿部高明, 海野倫明, 徳井太郎: "有機アニオントランスポーター oatp/Lstとその機能"蛋白核酸酵素. 46. 612-620 (2001)

    • Related Report
      2001 Annual Research Report

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

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