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STUDY ON EFFECTIVE COMBINATION AND ENHANCED EFFECTS OF ANTICANCERDRUGS

Research Project

Project/Area Number 60440050
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field Pediatrics
Research InstitutionMIE UNIVERSITY

Principal Investigator

SAKURAI Minoru  MIE UNIVERSITY,SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (40024707)

Co-Investigator(Kenkyū-buntansha) ARAI Shojiro  MIE UNIVERSITY,SCHOOL OF MEDICINE, ASSISTANT, 医学部, 助手 (40167979)
KOMADA Yoshihiro  MIE UNIVERSITY,SCHOOL OF MEDICINE, ASSISTANT, 医学部, 助手 (80186791)
井口 光正  三重大学, 医学部, 助手 (70135432)
井戸 正流  三重大学, 医学部, 助手 (90167263)
Project Period (FY) 1985 – 1988
Project Status Completed (Fiscal Year 1988)
Budget Amount *help
¥17,200,000 (Direct Cost: ¥17,200,000)
Fiscal Year 1988: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1987: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1986: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1985: ¥11,000,000 (Direct Cost: ¥11,000,000)
KeywordsNucleic acid metabolism / Intracellular active metabolite / Protein Kinase C / Phorbor esters / 多剤耐性 / Biochemical modulation / Collateral sensitivity / プロティンキナーゼC / ホルボールエステルレセプター / 高速液体クロマトグラフィ / MTX-5FU併用療法 / 6MP,6TG / ara-C / 抗癌剤 / 耐性克服 / 併用療法 / 高速液体クロマトグラフィ法 / 膜輸送
Research Abstract

1. To clarify the therapeutic efficacy of anticancer combination chemotherapy, we analyzed intracellular active metabolites of drugs, and effects of these drugs on nucleic acid metabolism with high performance liquid chromatography. After treatment with methotrexate, reduction of intracelluar ATP, GTP, dTTP and dCTP levels were observed. Ara-C had significant effects on the growth of cells at the higher level of ara-CTP than of dCTP. So the dCTP/ara-CTP ratio is one of very important factors in ara-C cytotoxicity. The increased production of intracellular fluoro-UTP(FUTP) and ara-CTP by pretreatment with MTX were recognized. These enhanced effects were based on biochemical modulation in each grugs. VP16 and Ara-C combination chemotherapy showed similar modulation effects. 6TG was metabolized to 6-thioGMP, GDP, GTP. Major products of 6MP, however, was 6-thioIMP. Small quantity of 6-thioGMP was detected, but no 6-thioGDP, GTP were produced. The intracellular levels of ATP and GTP pools decreased after treatment with 6TG and 6MP. Intracellular dCTP, and dTTP pools have declined after exposure to 6TG, whereas not decline with 6MP. These results suggested that cytotoxic mechanism of 6TG include inhibition of both purine pathway and DNA synthesis and 6MP only inhibits purine pathway.
2. Protein kinase C and phorbor diester receptor were related with pleiotropic drug resistance. Phorbor esters, also, were linked to the glucocorticoid-induced growth inhibition.

Report

(5 results)
  • 1988 Annual Research Report   Final Research Report Summary
  • 1987 Annual Research Report
  • 1986 Annual Research Report
  • 1985 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] 登勉: 臨床血液. 27. 1460-1467 (1986)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masaru,Ido: Cancer Res.47. 3460-3463 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] 落合秀江: 日本小児血液学会. 2. 61-67 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Toshiki,Ookubo: European J.of Cancer and Clin.Onco.24. 1823-1828 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masamune,Higashigawa: Leukemia Res.(1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masamune,Higashigawa: Med.Onco.and Tumor Phamacother. 5. 265-271 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Kunihiko Satoh: Leukemia Res.12. 3-9 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masaru Ido: Leukemia Res.(1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Minoru,Sakurai: "Intracellular pharmacokinetics of methotrexate and its effect on nucleotide pools in leukemic cells,In:Methotrexate in Cancer Therapy" Raven Press, 9 (1986)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Hajime,Kawasaki: "Relationship between intracellar dCTP/Ara-CTP ratio and cytotoxic effect of ara-C.In;Purine and pyrimidine metabolism in man V." Plenum Publishing Corp.,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] 川崎肇: "癌治療の進歩ー薬剤耐性の機序とその克服、小児科学大系89年補追版" 中山書店, (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Tsutomu,Nobori: "Mechanism of Resistance to Anticancer Drugs and Trials of overcome Their Resistance" Jpn J.Clin. Heamatol.27,. 1460-1467 (1986)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masaru,Ido: "Decreased phorbol Phorbor Ester Receptor and Protein Kinase C in P388 Murine Leukemic Cells Resistant to Etoposide" Cancer Res..47,. 3460-3463 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Hidee,Ochiai: "Studies on the active metabolites of thiopurines" Japanese Journal of Pediatric Hematology. 2. 61-67 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Toshiki,Ookubo: "Sequence-dependent antitumor effect of VP-16 and 1- -D-arabinofuranosylcytosine in L1210 ascites tumor" European J.of Cancer and Clin. Onco.24. 1823-1828 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masamune,Higashigawa: "Icreased sensitivity to 1- -D-arabinofuranosylcytosine in P388 murine leukemic cells resistant to etoposide." Leukemia Research. (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masamune,Higashigawa: "Incorporation of N4-behenoyl-1-B-D-arabinofuranosylcytosine into DNA as 1- -D-arabinofuranosylcytosine" Med. Onco. and Tumor Phamacother.5. 265-27 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Kunihiko,Satoh: "Phorbor esters potentiate glucocorticoid-induced cytotoxicity in CEM-C7 human T-leukemia cell line" Leukemia Res.,. 12. 3-9 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Masaru,Ido: "Phorbor esters potentiate glucocorticoid-induced cytotoxicity in CEM-C7 human T-leukemia cell line," Leukemia Res.(1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Minoru,Sakurai: Intracellular pharmacokinetics of methotrexate and its effect on nucleotide pools in leukemic cells, In:Methotrexate in Cancer Therapy. Raven Press, New York, 39-47 (1986)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Hajime,Kawasaki: Relationship between intracellar dCTP/Ara-CTP ratio and cytotoxic effect of ara-C In; Purine and pyrimidine metabolism in man V,W.L.Nyhan, L.F.Thompson and R.W.E.Watts, ed.Plenum Publishing Corp, (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Hajime,Kawasaki: Progress in Cancer treatment-Mechanisms of Resistance to drugs and Trials to overcome their resistance in New Encyclopedia of Pediatrics and Related Medical Sciences.Nakayama Shoten, (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] 落合秀江: 日本小児血液学会. 2. 61-67 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Toshiki Ookubo: European J.of Cancer and Clin.Onco.24. 1823-1828 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Masamune Higashigawa: Leukemia Research. (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Masamune Higashigawa: Med.Onco.and Tumor Phamacother.5. 265-271 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Kunihiko Satoh: Leukemia Research. 12. 3-9 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Masaru Ido: Leukemia Research. (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Masaru Ido: Cancer Research. 47. 3460-3463 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Masaru Ido: Leukemic Research. 10. 1063-1069 (1986)

    • Related Report
      1987 Annual Research Report
  • [Publications] Masaru Ido: Cancer Research.

    • Related Report
      1987 Annual Research Report
  • [Publications] 落合 秀江: 三重医学. 31. 505-516 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Tsutomu Nobori: Adv.Exp Med. 195. 475-480 (1986)

    • Related Report
      1986 Annual Research Report
  • [Publications] 川崎肇: 医学のあゆみ. 137. 1019 (1986)

    • Related Report
      1986 Annual Research Report
  • [Publications] 櫻井實: 日本血液学会誌. 49. 661-669 (1986)

    • Related Report
      1986 Annual Research Report
  • [Publications] M.Sakurai: "Methotrexate in Cancer Therapy" Raven Press,New York, 307 (1986)

    • Related Report
      1986 Annual Research Report
  • [Publications] Leukemia Research. 9-10. (1985)

    • Related Report
      1985 Annual Research Report
  • [Publications] 癌と化学療法. 12-3. (1985)

    • Related Report
      1985 Annual Research Report
  • [Publications] 癌と化学療法. 12-4. (1985)

    • Related Report
      1985 Annual Research Report
  • [Publications] 医学のあゆみ. 128-3. (1984)

    • Related Report
      1985 Annual Research Report

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Published: 1987-03-31   Modified: 2016-04-21  

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