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新しい分化誘導療法剤の開発と分化誘導療法の基礎的研究

Research Project

Project/Area Number 01010074
Research Category

Grant-in-Aid for Cancer Research

Allocation TypeSingle-year Grants
Research InstitutionResearch Institute for Clinical Oncology, Saitama Cancer Center

Principal Investigator

穂積 本男  埼玉県立がんセンター研究所, 副所長 (50113478)

Co-Investigator(Kenkyū-buntansha) 武市 紀年  北海道大学, 医学部, 助教授 (40002133)
水野 左敏  国立予防衛生研究所, 抗生物質部, 部長 (60072930)
斎藤 政樹  自治医科大学, 医学部, 教授 (60012762)
須田 立雄  昭和大学, 歯学部, 教授 (90014034)
高久 史麿  東京大学, 医学部, 教授 (40048955)
Project Period (FY) 1989
Project Status Completed (Fiscal Year 1989)
Budget Amount *help
¥12,900,000 (Direct Cost: ¥12,900,000)
Fiscal Year 1989: ¥12,900,000 (Direct Cost: ¥12,900,000)
Keywords分化誘導療法 / D因子 / アルキルエーテル非燐脂質 / 分化誘導療法補強剤 / シアロ糖化合物 / 熱ショック蛋白質 / 倍数性骨髄性白血病株細胞 / 活性化酸素
Research Abstract

分化誘導療法開発のために臨床応用可能な新規分化誘導剤を検索し、分化誘導剤の臨床応用への基礎的諸条件を検討して次の研究成果を得た。 1.新規分化誘導剤の開発:骨髄性白血病細胞(M1)蛋白質性分化誘導因子(D因子)の遺伝子をクローニングし、組換えD因子の生産に成功した(穂積)。また、新規化学合成アルキルエーテル非燐脂質が前骨髄球性白血病細胞に対して強い分化誘導と増殖抑制活性を示すことを見出した(穂積)。 2.分化誘導療法補強剤の開発:TGFーβおよびステロイドホルモンとTNFとの併用(武田)、GーCSFとレチノイン酸との併用(穂積)が骨髄性白血病細胞の分化誘導を増強すること、ハービマイシンAとNGFとの併用が褐色腫細胞の分化誘導を促進することを見出した(水野)。また、正常肺組織から単球性白血病細胞の増殖抑制因子(G1因子)が産生されることを見出し、その性質を明らかにした(穂積)。 3.分化誘導剤の作用機序:GーCSF,GM-CSF,M-CSF,IL-3が好中球および単球機能を活性化すること(高久)、D因子とILー6が骨代謝を修飾すること(須田、穂積)、シアロ糖化合物が細胞膜レセプターを介して骨髄性白血病細胞を合化誘導すること(斎藤)、癌遺伝子(cーmyc)がフレンド白血病細胞の増殖分化を制御すること(帯刀)、熱ショック蛋白質(hsp47)が胚性腫瘍細胞の分化誘導機序に関与すること(永田)を明らかにした。 4.実験動物による骨髄性白血病分化誘導療法の基礎的検討:マウスの倍数性骨髄性白血病株細胞(LLー2)を樹立し、この細胞を用いてin vivoの分化誘導剤に対する反応性と分化誘導剤による白血病マウスの治療効果を明らかにした。また、分化誘導剤耐性のラット骨髄性白血病細胞が宿主マクロファージ由来の活性化酸素によって分化し、増殖が抑制されることを確認した。

Report

(1 results)
  • 1989 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Lowe,D.G.: "Genomic cloning and heterologous expression of human differentiation-stimulating factor." DNA. 8. 351-539 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Honma,Y.: "Induction of differentiation of myeloid leukemia cells by novel alkylether lipids." Lipids.

    • Related Report
      1989 Annual Research Report
  • [Publications] Nakamaki,T.: "Granulocyte-colony stimulating factor and retinoic acid cooperatively induce granulocytic differentiation of acute promyelocytic leukemia cells in vitro." Japanese Journal of Cancer Research. 80. 1077-1082 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Ikuta,T.: "Normal mouse lung tissue produces a growth inhibitory factor(s)preferential for mouse monocytic leukemia cells." Cancer Immunology and Immunotherapy. 30. 139-144 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Hayashi,M.: "A new experimental model for in vivo studies on differentiation and proliferation of leukemic cells using a mouse myeloid leukemia aneuploid line." Leukemia Research. 13. 989-999 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Hino,M.: "Characterization of cellular receptors for erythroid differentiation factor on murine erythroleukemia cells." Journal of Biological Chimistry. 264. 10309-10314 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Yuo,A.: "Recombinant human granulocyte colony-stimulating factor as an activator of human granulocytes:Potentiation of responses triggered by receptor-mediated agonists and stimulation of C3bi receptor expression and adherence." Blood. 74. 2144-2149 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Kume,T.-U.: "Probability that the commitment of murine erythroleukemia cell differentiation is determined by the c-myc level." Journal of Molecular Biology. 202. 779-786 (1988)

    • Related Report
      1989 Annual Research Report
  • [Publications] Yamamoto,T.: "A balance between self-renewal and commitment in the murine erythroleukemia cells with the transferred c-myc gene;an in vitro stochastic model." Cell Differentiation & Development.

    • Related Report
      1989 Annual Research Report
  • [Publications] Kamijo,R.: "Suppression of TNF-stimulated proliferation of diploid fibroblasts and TNF-induced cytotoxicity against transformed fibroblasts by TGF-β." Biochemical Biophysical Research Communications. 158. 155-162 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Kamijo,R.: "Effect of combinations of transforming growth factor-β1 and TNF on induction of differentiation of human myelogenous leukemic cell lines." Jouranl of Immunology.

    • Related Report
      1989 Annual Research Report
  • [Publications] Nakamura,M.: "Characteristic incorporation of ganglioside GM3, which induces monocytic differentiation to human myelogenous leukemia HL-60 cells." Biochemical Biophysical Research Communications. 161. 782-789 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Kitagawa,S.: "Human myelogenous leukemia cell line HL-60 cells resistant to differentiation-induction by retinoic acid: Hyposialylation of glycosphingolipids and granulocytic differentiation by neolacto-series gangliosides." Journal of Biological Chemistry. 264. 16149-16154 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Motoyoshi,K.: "Recombinant and native human urinary colony-stimulating factor directly augments granulocytic and granulocyte-macrophage colony-stimulating factor production of human peripheral blood monocytes." Experimental Hematology. 17. 68-71 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Suzu,S.: "Enhancing effect of human monocytic colony-stimulating factor on monocyte tumoricidal activity." Cancer Research. 49. 5913-5917 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Ohsaka,A.: "In vivo activation of human neutrophil functions by administration of recombinant human granulocyte colony-stimulating factor in patients with malignant lymphoma." Blood. 74. 2743-2748 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Abe,E.: "A differentiation-inducing factor produced by the osteoblastic cell line MC3T3-E1 stimulates bone resorption by promoting osteoclast formation." Journal of Bone and Mineral Research. 3. 635-645 (1988)

    • Related Report
      1989 Annual Research Report
  • [Publications] Miyaura,C.: "Production of interleukin 6 and its relation to the macrophage differentiation of mouse myeloid leukemia cells(M1) treated with differentiation-inducing factor and 1α, 25-dihydroxyvitamin D3." Biochemical Biophysical Research Communications. 158. 660-666 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Uehara,Y.: "Irreversible inhibition of v-src tyrosine kinase activity by herbimycin A and its abrogation by sulfhydryl compounds." Biochemical Biophysical Research Communications. 163. 803-809 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Nakai,A.: "The transformation-sensitive heat shock protein(hsp47)binds specifically to fetuin." Biochemical Biophysical Research Communications. 164. 259-264 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Ohtsuka,K.: "A 40-kDa protein induced by heat shock and other stresses in mammalian and avian cells." Biochemical Biophysical Research Communications. 166. 642-647 (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Nakai,A.: "Transformation of BALB/3T3 cells by simian virus 40 cause a decreased synthesis of a collagen-binding protein(hsp47)." Journal of Biological Chemistry.

    • Related Report
      1989 Annual Research Report
  • [Publications] Nakai,A.: "A novel ATP-binding heat inducible protein of Mr=37,000 that is sensitive to transformation in BALB/3T3 cells." Journal of Cellular Physiology.

    • Related Report
      1989 Annual Research Report
  • [Publications] Michishita,M.: "Induction of tumor necrosis factor-alpha and its receptors during differentiation in myeloid leukemia cells along the monocytic pathway.A possible regulatory mechanism for TNF-alpha production." Journal of Biological Chemistry.

    • Related Report
      1989 Annual Research Report
  • [Publications] Fujii,Y.: "An enhanced expression of major histocompatibility complex class I and class II antigens in a lipopolysaccharide-resistant subline of a rat myelomonocytic leukemia." Cancer Research.

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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