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Investigations of mechanisms of drug-resistance in leukemia cells

Research Project

Project/Area Number 13671076
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionJichi Medical School

Principal Investigator

NAGAI Tadashi  Jichi Medical School, Faculty of Medicine, Assistant Professor, 医学部, 講師 (40237483)

Co-Investigator(Kenkyū-buntansha) OHMINA Ken  Jichi Medical School, Faculty of Medicine, Research Associate, 医学部, 助手 (90316521)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsChronic Myelogeneous leukemia / Drug resistance / imatinib / R115777 / RAS / KCL22 / SR / K562 / KU812 / Farnesyltransferase阻害剤 / STI571 / ascorbic acid / Nrf2 / γ-GCS
Research Abstract

Drug resistance is a major problem for patients with chronic myelogeneous leukemia in blast crisis who are being treated with the BCR/ABL tyrosine kinase inhibitor imatinib. To determine the mechanisms of imatinib-resistance and to examine the cytotoxic effect of a combination of a farnesyltransferase inhibitor, R115777, and imatinib on the imatinib-resistant cells, we have cloned three imatinib-resistant BCR/ABL-positive cell lines, KCL22/SR, K562/SR and KU812/SR. The level of phosphorylated BCR/ABL protein in these cells was suppressed by imatinib treatment, suggesting that deregulation of douwnstream of BCR/ABL kinase is involved in the resistance. DNA microarray analyses demonstrated that the RAS-MAPK signaling-related molecules RAS RASAP1 and RhoA, were up-regulated in KCL22/SR cells. Furthermore, the level of phospho-ERK1/2 was significantly suppressed in imatinib-sensitive parental KCL22 cells but was not changed in KCL22/SR cells by imatinib treatment. These results suggested that the aberrant activation of Ras-MAPK signaling is involved in the acquisition of resistance to imatinib. Treatment of KCL22/SR, K562/SR and KU812/SR cells with a combination of imatinib and R115777 resulted in synergistic inhibition of cell growth assessed by Isobologram of Steel and Peckham. This cell growth inhibition was, at least in part, due to the induction of apoptosis, while the treatment had no effect on the cell cycle. Furthermore, combined treatment with imatinib and a MEK1/2 inhibitor, U0126, also suppressed cell growth synergistically. These results suggest that the inhibition of RAS-MAPK signaling may restore the sensitivity to imatinib in some of imatinib-resistant cells.

Report

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

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Ohmine, K., Nagai T., et al.: "Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR"Stem Cells. 21. 315-321 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagai, T., et al.: "Oxidative stress is involved in hydroxyurea-induced erythroid differentiation"Br. J. Haematol.. 121. 657-661 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Komatsu, N., et al.: "A member of Forkhead transcription factor FKHRL1 is a downstream effector of ST1571-induced cell cycle arrest in BCR/ABL exprssing cells"J. Biol. Chem.. 278. 6411-6419 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 永井正: "CMLにおけるImatinib Mesylate(imatinib)療法とその耐性機序"血液・腫瘍科. 46. 237-241 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 永井正, 他: "STI571の耐性発現機序とその克服"血液・腫瘍科. 44. 22-27 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 永井正, 他: "2'-deoxycoformycinが奏効したhairy cell leukemia prolymphocytic variant"臨床血液. 43. 583-585 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohmine,K., Nagai,T., et al.: "Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR"Stem Cells. 21. 315-321 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagai,T., et al.: "Oxidative stress is involved in hydroxyurea-induced erythroid differentiation"Br.J.Haematol.. 121. 657-661 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Komatsu,N., et al.: "A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR/ABL expressing cells"J.Biol.Chem.. 278. 6411-6419 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagai,T.: "Imatinib mesylate (imatinib) therapy for CML and the mechanisms of resistance to the reagent (in Japanese)"Hematology & Oncology. 46. 237-241 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagai,T et al.: "Mechanisms of resistance to imatinib (in Japanese)"Hematology & Oncology. 44. 22-27 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagai,T., et al.: "Successful treatment of hairy cell leukemia prolymphocytic variant with 2'-deoxycoformycin (in Japanese)"Jon.J.Clin.Hematol.. 43. 583-585 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Komatsu, N.: "A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR/ABL expressing cells"J. Biol. Chem.. 278. 6411-6419 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagai, T.: "Oxidative stress is involved in hydroxyurea-induced erythroid differentiation"Br. J. Haematol.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohmine, K.: "Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR"STEM CELLS. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] 永井正: "CMLにおけるImatinib Mesylate(imatinib)療法とその耐性機序"血液・腫瘍科. 46(印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] 永井 正: "STI571の耐性発現機序とその克服"血液・腫瘍科. 44. 22-27 (2002)

    • Related Report
      2001 Annual Research Report

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

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