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Drug Resistance which ABCG2/BCRP contributes

Research Project

Project/Area Number 17590139
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionMeiji Pharmaceutical University

Principal Investigator

IKEGAMI Yoji  Meiji Pharmaceutical Universit, Lecturer, 薬学部, 講師 (50322524)

Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥2,900,000 (Direct Cost: ¥2,900,000)
KeywordsPharmacy / Cancer / Drug resistance
Research Abstract

1. Change of substrate specificity, according to single nucleotide polymorphisms (SNPs) of ABCG2/BCRP
It is thought that 141st amino acid mutation influences the translation as one of the causes of the relative resistance decreases seen with PC6/Q141K, and the protein expression decreased. However, the protein expression was expected and some factors were expected to exist to about 65% of PC-6/WT from about 35% it as for the decrease in the resistance degree. The 141st amino acid mutation appears especially at high frequency in the Japanese, and it is necessary to pursue this result further. Whether the 141st amino acid is an amino acid that exists in the ATP binding site, and the localization of the mutation might influences the function of ABCG2. Then, the mutation that exists in the ATP binding site and/or outside of cell, in the transmembrane domain was examined.
2. Expression of ABCG2/BCRP in clinical specimen
The amount of expression of ABCG2mRNA was observed among 12 samples examin … More ed by a real-time PCR analysis and an example that was remarkably higher in the cancer organization than the normal tissue and lower in the cancer organization than the normal tissue was observed. It was guessed that normal organization excretion of anti-cancer drug to protect itself by high expression of ABCG2 in the normal tissue. Moreover, examples were seen expression whose one of this level is almost higher than that of the normal tissue in three examples and the cancer organizations in the normal tissue and the cancer organization were two examples. A state and malignancy of cancer, stage classifications, and the lymph node metastasis were various in each patient, so that the correlation of expression amount of ABCG2mRNA and the malignancy of cancer were not detected.
3. Inhibition mechanism of ABCG2/BCRP inhibitor and examination of specificity
We showed that quercetin, nobobioshin, and ZD1839 inhibit the transport activity of ABCG2 strongly, and to overcome various anti-cancer drug resistance in the ABCG2 expression cell line. Then, the inhibition effect of the transport activity was examined by using the ABCG2 gene transfection membrane to examine these three kinds of drugs inhibit the transport activity of the CPT derivatives that showed the resistance to ABCG2 excessive expression cell, and whether overcome the resistance. As a result, three kinds of inhibitors strongly inhibit transport activity of each CPT derivatives. It was suggested that the CPT derivatives shows the resistance to ABCG2 excessive expression cell overcome the drug resistance by using these inhibitors together. Less

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (8 results)

All 2007 2006 2005

All Journal Article (8 results)

  • [Journal Article] Re-evaluation and functional classification of nonsynonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2.2007

    • Author(s)
      Tamura A., Wakabayashi K., Onishi Y., Takeda M., Ikegami Y., Sawada S., Tsuji M., Matsuda Y., Ishikawa T.
    • Journal Title

      Cancer Sci. 98

      Pages: 231-239

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Re-evaluation and functional classification of nonsynonymous single nucleotide polymorphisms of human ABC transporter ABCG2.2007

    • Author(s)
      Tamura A., Wakabayashi K., Onishi Y., Takeda M., Ikegami Y., Sawada S., Tsuji M., Matsuda Y., Ishikawa T.
    • Journal Title

      Cancer Sci. 98(2)

      Pages: 231-239

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer.2006

    • Author(s)
      Nakagawa H., Saito H., Ikegami Y., Aida-Hyugaji S., Sawada S., Ishikawa T.
    • Journal Title

      Cancer Lett. 234

      Pages: 81-89

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transport mechanism-based drug molecular design : Novel camptothecin analogues to circumvent ABCG2-associated drug resistance of human tumor cells.2006

    • Author(s)
      Ishikawa T., Ikegami Y., Sano K., Nakagawa H., Sawada S.
    • Journal Title

      Curr Pharm Des. 12

      Pages: 313-325

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer.2006

    • Author(s)
      Nakagawa H., Saito H., Ikegami Y., Aida-Hyugaji S., Sawada S., Ishikawa T.
    • Journal Title

      Cancer Lett. 234(1)

      Pages: 81-89

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Transport mechanism-based drug molecular design : Novel camptothecin analogues to circumvent ABCG2-associated drug resistance of human tumor cells.2006

    • Author(s)
      Ishikawa T., Ikegami Y., Sano K., Nakagawa H., Sawada S.
    • Journal Title

      Curr.Pharm.Des. 12(3)

      Pages: 313-325

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Gefitinib("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance.2005

    • Author(s)
      Nakamura Y., Oka M., Soda H., Shiozawa K., Yoshikawa M., Itoh A., Ikegami Y., Tsurutani J., Nakatomi K., Kitazaki T., Doi S., Yoshida H., Kohno S.
    • Journal Title

      Cancer Res. 65

      Pages: 1541-1546

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Gefitinib("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance.2005

    • Author(s)
      Nakamura Y, Oka M., Soda H., Shiozawa K., Yoshikawa M., Itoh A., Ikegami Y., Tsurutani J., Nakatomi K., Kitazaki T., Doi S., Yoshida H., Kohno S.
    • Journal Title

      Cancer Res. 65

      Pages: 1541-1546

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary

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Published: 2005-04-01   Modified: 2016-04-21  

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