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Development of novel therapeutic strategies based on the molecular analyses of tumor cells in animal lymphomas

Research Project

Project/Area Number 17380186
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Clinical veterinary science
Research InstitutionThe University of Tokyo

Principal Investigator

TSUJIMOTO Hajime  The University of Tokyo, Graduate School of Agricultural and Life Sciences, Professor (60163804)

Co-Investigator(Kenkyū-buntansha) OHNO Koichi  The University of Tokyo, Graduate Scholl of Agricultural and Life Sciences, Associate professor (90294660)
NAKAYAMA Hiroyuki  The University of Tokyo, Graduate Scholl of Agricultural and Life Sciences, Professor (40155891)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥15,900,000 (Direct Cost: ¥15,900,000)
Fiscal Year 2006: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2005: ¥11,400,000 (Direct Cost: ¥11,400,000)
Keywordsdog / lymphoid tumor / lymphoma / chemotherapy / drug resistance / minimal residual disease / MRD / animal model / mdr1 / p53 / 予後 / 分子病態 / P-糖タンパク / p53遺伝子
Research Abstract

For the past 30 years, a large number of therapeutic clinical trials for canine lymphoid tumors were reported; however, apparent improvement on the outcome of the patients has not been obtained. The present study was carried out to aim at the development of novel therapeutic strategies based upon the molecular analyses of the tumor cells.
With respect to the drug resistance of the tumor cells, drug efflux pumps, drug metabolizing molecules, cell cycle-regulating molecules, and apoptosis-associated molecules were examined. The results indicated that increased expression of P-glycoprotein (P-gp), one of the drug efflux pump, and mutation of p53 gene encoding cell cycle/apoptosis-associated molecule were found in drug-resistant lymphoid tumors in dogs.
Next, we established an assay system to quantify the copy number of rearranged immunoglobulin and T-cell receptor genes in lymphoid cells. The assay system enabled the quantification of a small number of residual tumor cells after chemotherapy, namely minimal residual disease (MRD). MRD could be detected in dogs even after induction of complete remission and gradually increased 1~2 months before relapse. The amount of MRD at the end of chemotherapy was negatively correlated with the remission duration until relapse. These findings indicated that the MRD could be an objective marker to compare the efficacy of different chemotherapeutic protocols and a negative prognostic factor for the relapse in canine lymphoma. Furthermore, the present study introduced a tailor-made therapy based on the MRD level in each phase/patient.
Because the lymphoid tumors in dogs can be recognized as an animal model of the human disease, the present study provided useful information to develop novel therapeutic strategies in lymphoid tumors in humans.

Report

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

    (52 results)

All 2010 2009 2008 2007 2006 2005 Other

All Journal Article (44 results) (of which Peer Reviewed: 18 results) Presentation (8 results)

  • [Journal Article] Molecular cytogenetic analysis of feline leukemia virus insertions in cat lymphoid tumor cells.2010

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

      Journal of Virological Methods 163

      Pages: 344-352

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Long term survival of primary skeletal muscle lymphoma in a Miniature dachshund.2010

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

      Journal of Veterinary Medical Science (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] A case of canine lymphomatoid granulomatosis with cutaneous lesions.2010

    • Author(s)
      Shimazaki, T, et al.
    • Journal Title

      Journal if Veterinary Medical Science (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Monitoring of minimal residual disease (MRD) after multidrug chemotherapy and its correlation to outcome in dogs with lymphoma : a proof-of-concept pilot study.2010

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

      Journal of Veterinary Internal Medicine (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Quantitative analysis of mRNA for 10 different drug resistance factors in dogs with lymphoma.2010

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

      Journal of Veterinary Medical Science (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Molecular cytogenetic analysis of feline leukemia virus insertions in cat lymphoid tumor cells2010

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

      Journal of Virological Methods 163

      Pages: 344-352

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Long term survival of primary skeletal muscle lymphoma in a Miniature dachshund2010

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

      Journal of Veterinary Medical Science (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A case of canine lymphomatoid granulomatosis with cutaneous lesions2010

    • Author(s)
      Shimazaki, T., et al.
    • Journal Title

      Journal of Veterinary Medical Science (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Monitoring of minimal residual disease(MRD)after multidrug chemotherapy and its correlation to outcome in dogs with lymphoma : A proof-of-concept pilot study2010

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

      Journal of Veterinary Internal Medicine (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Quantitative analysis of mRNA for 10 different drug resistance factors in dogs with lymphoma2010

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

      Journal of Veterinary Internal Medicine (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Myelodysplastic syndrome and acute myeloid leukemia in cats infected with feline leukemia virus clone 33 containing a unique long terminal repeat.2009

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

      International Journal of Cancer 124

      Pages: 1133-1141

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Quantitative analysis of mRNA transcripts of Hox, SHH, PTCH, Wnt, and Fzd genes in canine hematopoietic progenitor cells and various in vitro colonies differentiated from the cells.2009

    • Author(s)
      Ide, K, et al.
    • Journal Title

      Journal of Veterinary Medical Science 71

      Pages: 69-77

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Identification of a novel common proviral integration site, flit-1, in feline leukemia virus induced thymic lymphoma.2009

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

      Virology 30

      Pages: 16-22

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Identification of cancer stem cells in a Tax-transgenic (Tax-Tg) mouse model of adult T-cell leukemia/lymphoma (ATL).2009

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

      Blood 114

      Pages: 2709-2720

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Semsitivity for the detection of a clonally rearranged antigen receptor gene in endoscopically obtained biopsy specimens from canine alimentary lymphoma.2009

    • Author(s)
      Fukushima, K, et al.
    • Journal Title

      Journal of Veterinary Medical Science 71

      Pages: 1673-1676

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Myelodysplastic syndrome and acute myeloid leukemia in cats infected with feline leukemia virus clone 33 containing a unique long terminal repeat2009

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

      International Journal of Cancer 124

      Pages: 1133-1141

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Quantitative analysis of mRNA transcripts of Hox, SHH, PTCH Wnt, and Fzd genes in canine hematopoietic progenitor cells and various in vitro colonies differentiated from the cells2009

    • Author(s)
      Ide, K., et al.
    • Journal Title

      Journal of Veterinary Medical Science 71

      Pages: 69-77

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Identification of a novel common proviral integration site, flit-1, in feline leukemia virus induced thymic lymphoma2009

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

      Virology 30

      Pages: 16-22

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Identification of cancer stem cells in a Tax-transgenic(Tax-Tg)mouse model of adult T-cell leukemia/lymphoma(ATL)2009

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

      Blood 114

      Pages: 2709-2720

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Semsitivity for the detection of a clonally rearranged antigen receptor gene in endoscopically obtained biopsy specimens from canine alimentary lymphoma2009

    • Author(s)
      Fukushima, K., et al.
    • Journal Title

      Journal of Veterinary Medical Science 71

      Pages: 1673-1676

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Modest effect of impaired P-glycoprotein on the plasma concentration of fexofenadine, quinidine, and loperamide following oral administration in collies.2008

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

      Drug Metabolism and Disposition 36

      Pages: 807-810

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Molecular pathogenesis of feline leukemia virus-induced malignancies : Insertional mutagenesis.2008

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

      Veterinary Immunology and Immunopathology 123

      Pages: 138-143

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Investigation of various methods for the cryopreservation of canine bone marrow-derived CD34^+ cells.2008

    • Author(s)
      Ide, K, et al.
    • Journal Title

      Journal of Veterinary Medical Science 70

      Pages: 1211-1217

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Quantitative assessment of minimal residual disease (MRD) in canine lymphoma by using real-time polymerase chain reaction.2008

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

      Veterinary Immunology and Immunopathology 126

      Pages: 321-331

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Modest effect of impaired P-glycoprotein on the plasma concentration of fexofenadine, quinidine, and loperamide following oral administration in collies2008

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

      Drug Metabolism and Disposition 36

      Pages: 807-810

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Molecular pathogenesis of feline leukemia virus-induced malignancies : Insertional mutagenesis2008

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

      Veterinary Immunology and Immunopathology 123

      Pages: 138-143

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Investigation of various methods for the cryopreservation of canine bone marrow-derived CD34^+ cells2008

    • Author(s)
      Ide, K., et al.
    • Journal Title

      Journal of Veterinary Medical Science 70

      Pages: 1211-1217

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Induction of chemoresistance in a canine cultured cell line by retroviral transduction of the canine multidrug resistance 1 gene (mdr1).2007

    • Author(s)
      Matsuura, S, et al.
    • Journal Title

      American Journal of Veterinary Research 68

      Pages: 95-100

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Induction of chemoresistance in a canine cultured cell line by retroviral transduction of the canine multidrug resistance 1 gene(mdr 1)2007

    • Author(s)
      Matsuura, S., et al.
    • Journal Title

      American Journal of Veterinary Research 68

      Pages: 95-100

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Induction of chemoresistance in a canine cultured cell line by retroviral transduction of the canine multidrug resistance 1 gene(mdr1).2007

    • Author(s)
      Matsuura, S., et al.
    • Journal Title

      Am. J. Vet. Res. 68

      Pages: 95-100

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Molecular cloning of feline lung resistance-related protein (LRP) cDNA and its expression in a feline lymphoma cell line and adriamycin-resist ant subline.2006

    • Author(s)
      Fukushima, K, et al.
    • Journal Title

      Journal of Veterinary Medical Science 68

      Pages: 885-890

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Establishment and characterization of primary canine hepatocellular carcinoma cell lines producing alpha-fetoprotein.2006

    • Author(s)
      Kawarai, S., et al.
    • Journal Title

      Vet. Immunol. Immunopathol. 113

      Pages: 30-36

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Prognostic factors associated with survival in dogs with lymphocytic-plasmacytic enteritis.2006

    • Author(s)
      Ohno, K., et al.
    • Journal Title

      J. Vet. Med. Sci. 68

      Pages: 929-933

    • NAID

      110004809492

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Essential thrombocythemia in a dog.2006

    • Author(s)
      Mizukoshi, T., et al.
    • Journal Title

      J. Vet. Med. Sci. 68

      Pages: 1203-1206

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Transcriptional control of BubR1 by P53 and suppression of centrosome amplification by BubR1.2005

    • Author(s)
      Oikawa, T, et al.
    • Journal Title

      Molecular and Cellular Biology 25

      Pages: 4046-4061

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Detection of centrosome amplification as a surrogate marker of dysfunction in p53 pathway-p53 gene mutation or MDM2 overexpression.2005

    • Author(s)
      Kaneko, N, et al.
    • Journal Title

      Veterinary and Comparative Oncology 3

      Pages: 203-210

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Transcriptional control of BubR1 by P53 and suppression of centrosome amplification by BubR12005

    • Author(s)
      Oikawa, T., et al.
    • Journal Title

      Molecular and Cellular Biology 25

      Pages: 4046-4061

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Detection of centrosome amplification as a surrogate marker of dysfunction in p53 pathway-p53 gene mutation or MDM2 overexpression2005

    • Author(s)
      Kaneko, N., et al.
    • Journal Title

      Veterinary and Comparative Oncology 3

      Pages: 203-210

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Molecular cloning of feline lung resistance-related protein(LRP)cDNA and its expression in a feline lymphoma cell line and adriamycin-resistant subline2005

    • Author(s)
      Fukushima, K, et al.
    • Journal Title

      Journal of Veterinary Medical Science 68

      Pages: 885-890

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] High expression of Bcl-xL in delayed apoptosis of canine neutrophils induced by lopopolysaccharide.2005

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

      Res.Vet.Sci. 78

      Pages: 183-187

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Transcriptional control of BubR1 by p53 and suppression of centrosome amplification by BubR1.2005

    • Author(s)
      Oikawa, T. et al.
    • Journal Title

      Mol.Cell.Biol. 25

      Pages: 4046-4061

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Cloning of cDNA encoding canine endothelin receptors and their expression in normal tissues.2005

    • Author(s)
      Yasuda, N. et al.
    • Journal Title

      J.Vet.Med.Sci. 67

      Pages: 1075-1079

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Detection of centrosome amplification as a surrogate marker of dysfunction in p53 pathway-p53 gene mutation or MDM2 overexpression.2005

    • Author(s)
      Kaneko, N. et al.
    • Journal Title

      Vet.Comp.Oncol. 3

      Pages: 203-210

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Quantitative assessment of minimal residual disease(MRD)in canine lymphoma by using real-time polymerase chain reaction

    • Author(s)
      Junpei Yamazaki, et al.
    • Journal Title

      Veterinary Immunology and Immunopathology 126

      Pages: 321-331

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Quantification of minimal residual disease (MRD) using real-time polymerase chain reaction in canine lymphoma.2006

    • Author(s)
      Yamazaki, J, et al.
    • Organizer
      26^th Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain, Georgia, U.S.A.
    • Year and Date
      2006-10-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Evaluation of P-glycoprotein function in tumor cells and its relation to drug resistance in canine lymphoma.2006

    • Author(s)
      Kishida, Y, et al.
    • Organizer
      26^th Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain, Georgia, U.S.A
    • Year and Date
      2006-10-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Peculiar clinical features of lymphoma in miniature dachsfund dogs.2006

    • Author(s)
      Setoguchi, A, et al.
    • Organizer
      26^th Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain, Georgia, U.S.A.
    • Year and Date
      2006-10-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] A proposal for the prognostic scoring system in canine lymphoma.2006

    • Author(s)
      Morino, T, et al.
    • Organizer
      26^th Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain, Georgia, U.S.A.
    • Year and Date
      2006-10-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Quantification of minimal residual disease(MRD)using real-time polymerase chain reaction in canine lymphoma2006

    • Author(s)
      Yamazaki, J., et al.
    • Organizer
      26^<th> Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain, Georgia, U.S.A.
    • Year and Date
      2006-10-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Evaluation of P-glycoprotein function in tumor cells and its relation to drug resistance in canine lymphoma2006

    • Author(s)
      Kishida, Y., et al.
    • Organizer
      26^<th> Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain, Georgia, U.S.A.
    • Year and Date
      2006-10-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] Peculiar clinical features of lymphoma in miniature dachsfund dogs2006

    • Author(s)
      Setoguchi, A., et al.
    • Organizer
      26^<th> Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain, Georgia, U.S.A.
    • Year and Date
      2006-10-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Presentation] A proposal for the prognostic scoring system in canine lymphoma2006

    • Author(s)
      Morino, T., et al.
    • Organizer
      26^<th> Annual Conference of the Veterinary Cancer Society
    • Place of Presentation
      Callaway Gardens Pine Mountain
    • Year and Date
      2006-10-22
    • 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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