1989 Fiscal Year Annual Research Report

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 Institution	Research 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)
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。

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)
[Publications] Honma,Y.: "Induction of differentiation of myeloid leukemia cells by novel alkylether lipids." Lipids.
[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)
[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)
[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)
[Publications] Hino,M.: "Characterization of cellular receptors for erythroid differentiation factor on murine erythroleukemia cells." Journal of Biological Chimistry. 264. 10309-10314 (1989)
[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)
[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)
[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.
[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)
[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.
[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)
[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)
[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)
[Publications] Suzu,S.: "Enhancing effect of human monocytic colony-stimulating factor on monocyte tumoricidal activity." Cancer Research. 49. 5913-5917 (1989)
[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)
[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)
[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)
[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)
[Publications] Nakai,A.: "The transformation-sensitive heat shock protein(hsp47)binds specifically to fetuin." Biochemical Biophysical Research Communications. 164. 259-264 (1989)
[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)
[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.
[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.
[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.
[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.

1989 Fiscal Year Annual Research Report

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

Principal Investigator

穂積 本男 埼玉県立がんセンター研究所, 副所長 (50113478)

Research Products

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

[Publications] Honma,Y.: "Induction of differentiation of myeloid leukemia cells by novel alkylether lipids." Lipids.

[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)

[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)

[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)

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

[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)

[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)

[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.

[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)

[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.

[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)

[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)

[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)

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

[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)

[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)

[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)

[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)

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

[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)

[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.

[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.

[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.

[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.

穂積本男埼玉県立がんセンター研究所, 副所長 (50113478)