1995 Fiscal Year Annual Research Report

がん増悪因子とその制御に作用する制がん物質の研究

Research Project

Project/Area Number	06282122
Research Institution	国立予防衛生研究所
Principal Investigator	上原至雅国立予防衛生研究所, 生物活性物質部, 室長 (50160213)
Co-Investigator(Kenkyū-buntansha)	井本正哉慶応義塾大学, 理工学部, 助教授 (60213253) 岡田信子国立がんセンター研究所, 主任研究官 (70194363) 小河原宏明治薬科大学, 教授 (00097198) 岡部實裕北海道大学, 医学部・附属病院, 助手 (40113534) 沖俊一富山県立大学, 工学部, 教授 (40264676)
Keywords	がん遺伝子 / シグナル伝達 / 制がん物質 / がん抑制遺伝子 / IL-6 / 転移 / 血管新生 / 薬剤耐性
Research Abstract	1.非接着性ポリマーを用いた足場非依存増殖の定量をヒト上皮由来のがん細胞でも検討し、がん化シグナル抑制物質探索への有用性を示した。 2.がん化シグナルに作用する物質の探索から得たエンジェルマイシンの化学構造を決定し、アザチロシンの分子標的を解析した。 3.CMLの進展にDNAメチル化の異常が高頻度にみられること、活性なPI3-kinaseに結合する蛋白質リン酸化酵素の存在を示した。 4.細胞周期においてサイクリンD1の過剰発現がG1期を短縮させる機構と、RB欠損のがん細胞を選択的にアポトーシス誘導する新規化合物の作用を解析した。 5.IL-6の活性修飾物質の探索から新規化合物を見いだし、悪液質抑制効果を観察した。また、IL-6刺激により、Stat3がCRE類似部位結合性36kDa分子と複合体を形成することを見いだした。 6.RGDS誘導体の中に転移を抑制する化合物を見いだしその分子機構を解析し、リゾキシンの血管新生阻害作用が血管内皮機能の抑制によることを示した。 7.ヒト結腸がん5-FU耐性細胞の耐性機構を解析し、薬剤接触時間の違いが感受性を変化させること、また、多剤耐性がん細胞へM-CSF遺伝子を導入することで転移抑制効果が得られることを示した。

Research Products

(43 results)

All Other

All Publications (43 results)

[Publications] Fukazawa, H.: "A microplate assay for quantitation of anchorage-independent growth of transformed cells." Anal. Biochem.228. 83-90 (1995)
[Publications] Hori, H.: "Structure of angelmicin B ; a novel src signal transduction inhibitor." Tettrahedron Lett.(in press).
[Publications] Yokoyama, K.: "Angelmicin B, a new inhibitor of oncogenic signal transduction, inhibits growth and induces of myelomonocytic differentiation of human myeloid leukemia HL-60 cells." Leukemia Res.(in press).
[Publications] Okabe, M.: "Establishment and characterization of a new Ph1-positive chronic myeloid leukemia cell line MC3 with trilineage phenotype and altered p53 gene." Leukemia and Lymphoma. 16. 493-505 (1995)
[Publications] Kunieda, Y.: "Effects of rhG-CSF on infection complication and impaired function of neutrophils secondary to chemotherapy for non-Hodgkin's lymphoma." Leukemia and Lymphoma. 16. 471-476 (1995)
[Publications] Okabe, M.: "Administration of rhG-CSF increases complete remission rates after CHOP and ProMACE/CytaBOM for non-Hodgkin's lymphoma : a pilot study." Leukemia and Lymphoma. 19. 485-491 (1995)
[Publications] Kurosawa, M.: "Analysis of p53 gene mutation in acute myelogenous leukemia : the p53 gene mutations associated with a deletion of chromosome 17." Ann. Hematol.71. 83-87 (1995)
[Publications] Okabe, M.: "Reversal effect of itraconazol on adriamycin- and etoposide-resistance in human leukemia cells." Ann. Hematol.(in press).
[Publications] Okabe, M.: "Megakaryocytic differentiation of leukemic cell line, MC3, by phorbol ester : Induction of glycoprotein IIb/IIIa and effects on expression of IL-6, IL-6 receptor, mpl and GATA genes." Leukemia Res.(in press).
[Publications] Machida, T.: "Cochlioquinone A, an inhibitor of diacylglycerol kinase." J. Antibiotics. 48. 1076-1080 (1995)
[Publications] Monden, Y.: "Stimulation of the expression of rhoB contributes to the ability of azatyrosine to convert c-erbB-2-transformed cells to a normal morphology." Oncogene Reports. 3. 49-55 (1996)
[Publications] Monden, Y.: "Azatyrosine inhibits the activation of c-raf-1, c-jun and AP-1 but not the activation of ras during signal transduction triggered by oncogenic c-erb-2." Oncogene Reports. 3. 33-44 (1996)
[Publications] Mizutani, Y.: "Induction of erythroid differentiation in leukemic K562 cells by an S-adenosylhomocysteine hydrolase inhibitor, aristeromycin." Biochem. Biophys. Res. Commun.207. 69-74 (1995)
[Publications] Ui, H.: "Inhibition of phosphatidylinositol-specific phospholipase C activity by fluvirucin B2." J. Antibiotics. 48. 387-390 (1995)
[Publications] Imoto, M.: "In situ inhibition of protein-tyrosine phosphatase by dephostatin." Cell. Pharmacol.2. 199-203 (1995)
[Publications] Ui, H.: "A novel cyclic lipoundecapeptide, pholipeptin, isolated from Pseudomonas Sp." Tetrahedron Lett.36. 7479-7480 (1995)
[Publications] Sakai, T.: "Absolute configuration of spicamycin, an antitumor antibiotic produced by Streptomyces alanosinicus." J. Antibiotics. 48. 899-900 (1995)
[Publications] Hayakawa, Y.: "Anguinomycins C and D, new antitumor antibiotics with selective cytotoxicity against transformed cells." J. Antibiotics. 48. 954-961 (1995)
[Publications] Hayakawa, Y.: "Selective cytotoxicity of mycophenolic acid against transformed cells." J. Antibiotics. 48. 1182-1184 (1995)
[Publications] Shin-ya, K.: "Novel neuronal cell protecting substances, aestivophoenins A and B, produced by Streptomyces purpeofuscus." J. Antibiotics. 48. 1378-1381 (1995)
[Publications] Komiyama, K.: "Lousianins A, B, C and D : Non-steroidal growth inhibitors of testosterone SC 115 cells. I. Taxonomy, Fermentation, Isolation and Biological Characteristics." J. Antibiotics. 48. 1086-1089 (1995)
[Publications] Takamatsu, S.: "Lousianins A, B, C and D : non-steroidal growth inhibitors of testosterone SC 115 cells. II. Physico-chemical properties and structural elucidation." J. Antibiotics. 48. 1090-1094 (1995)
[Publications] Hayashi, M.: "Macrosphelide, a novel inhibitor of cell-cell adhesion molecule. I. Taxonomy, fermentation, isolation and biological activities." J. Antibiotics. 48. 1435-1439 (1995)
[Publications] Takamatsu, S.: "Macrosphelide, a novel inhibitor of cell-cell adhesion molecule. II. Physicochemical properties and structure elucidation." J. Antibiotics. 49. 95-98 (1996)
[Publications] Hayashi, M.: "Chlovalicin, a new cytocidal antibiotic produced by Sphorothrix sp. FO-4649. I. Taxonomy, fermentation, isolation and biological activities." J. Antibiotics. (in press).
[Publications] Takamatsu, S.: "Chlovalicin, a new cytocidal antibiotic produced by Sphorothrix sp. FO-4649. II. Physicochemical properties and structural elucidation." J. Antibiotics. (in press).
[Publications] Nakae, K.: "ERM, a PEA3 subfamily of Ets transcription factors, cancooperate with c-Jun." J. Biol. Chem.270. 23795-23800 (1995)
[Publications] Nakajima, K.: "Signal transduction through IL-6 receptor : involvement of multiple protein kinases, Stat factors and a novel H-7-sensitive pathway." Ann. New York Acad. Sci.762. 55-70 (1995)
[Publications] Hibi, M.: "IL-6 family cytokine and signal transduction : a model of the cytokine system." J. Mol. Med.(1996)
[Publications] Kojima, H.: "IL-6-inducible complexes on an IL-6 response element of the junB promoter contain Stat3 and 36 kDa CRE-like site binding protein(s)." Oncogene. (in press).
[Publications] Yamanaka, Y.: "Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation." EMBO J.(in press).
[Publications] Yoneda, J.: "Role of the heparin-binding domain of chimeric peptides derived from fibronectin in cell spreading and motility." Exp. Cell Res.217. 169-179 (1995)
[Publications] Sato, K.: "Inhibition of tumor-induced angiogenesis by a synthetic lipid A analogue with low toxicity, DT-5461." Jpn. J. Cancer Res.86. 374-382 (1995)
[Publications] Fujii, H.: "Human melanoma invasion and metastasis enhancement by high expression of aminopeptidase N/CD13." Clin. Expl. Metastasis. 13. 337-344 (1995)
[Publications] Sato, K.: "A novel synthetic lipid A analogue with low endotoxicity, DT-5461, prevents lethal endotoxemia." Infect. Immun.63. 2859-2866 (1995)
[Publications] Mochizuki, M.: "Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20 (R)- and 20 (S)-ginsenoside-Rg3, of Red ginseng." Biol. Pharm. Bull.18. 1197-1202 (1995)
[Publications] Komazawa, H.: "Combination of anti-cell adhesive synthetic Arg-Gly-Asp-Ser analogue and anti-cancer drugs heightens their original anti-metastatic activities." Oncology Res.7. 341-351 (1995)
[Publications] Fujii, H.: "Antimetastatic activities of synthetic RGDS or RLDS peptide analogues and their inhibitory mechanisms." Biol. Pharm. Bull.18. 1681-1688 (1995)
[Publications] Oikawa, T.: "Depudecin, a microbial metabolite containing two epoxide groups, exhibits anti-angiogenic activity in vivo." Chem. Pharm. Bull.18. 1305-1307 (1995)
[Publications] Inaba, M.: "Reduced activity of anabolizing enzymes in 5-fluorouracil-resistant human stomach cancer cells." Jpn. J. Cancer Res.(in press).
[Publications] Inaba, M.: "In vitro-in vivo correlation in anticancer drug sensitivity test using AUC-based concentrations and collagen gel droplet-embedded culture." Oncology. (in press).
[Publications] Yano, S.: "Differential effects of anti-inflammatory cytokines (IL-4, IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor (MCAF)." J. Leukocyte Biol.57. 303-309 (1995)
[Publications] Yano, S.: "Novel metastasis model of human lung cancer in NK-cell depleted SCID mice." Int. J. Cancer.(in press).

1995 Fiscal Year Annual Research Report

がん増悪因子とその制御に作用する制がん物質の研究

Principal Investigator

上原 至雅 国立予防衛生研究所, 生物活性物質部, 室長 (50160213)

Research Products

[Publications] Fukazawa, H.: "A microplate assay for quantitation of anchorage-independent growth of transformed cells." Anal. Biochem.228. 83-90 (1995)

[Publications] Hori, H.: "Structure of angelmicin B ; a novel src signal transduction inhibitor." Tettrahedron Lett.(in press).

[Publications] Yokoyama, K.: "Angelmicin B, a new inhibitor of oncogenic signal transduction, inhibits growth and induces of myelomonocytic differentiation of human myeloid leukemia HL-60 cells." Leukemia Res.(in press).

[Publications] Okabe, M.: "Establishment and characterization of a new Ph1-positive chronic myeloid leukemia cell line MC3 with trilineage phenotype and altered p53 gene." Leukemia and Lymphoma. 16. 493-505 (1995)

[Publications] Kunieda, Y.: "Effects of rhG-CSF on infection complication and impaired function of neutrophils secondary to chemotherapy for non-Hodgkin's lymphoma." Leukemia and Lymphoma. 16. 471-476 (1995)

[Publications] Okabe, M.: "Administration of rhG-CSF increases complete remission rates after CHOP and ProMACE/CytaBOM for non-Hodgkin's lymphoma : a pilot study." Leukemia and Lymphoma. 19. 485-491 (1995)

[Publications] Kurosawa, M.: "Analysis of p53 gene mutation in acute myelogenous leukemia : the p53 gene mutations associated with a deletion of chromosome 17." Ann. Hematol.71. 83-87 (1995)

[Publications] Okabe, M.: "Reversal effect of itraconazol on adriamycin- and etoposide-resistance in human leukemia cells." Ann. Hematol.(in press).

[Publications] Okabe, M.: "Megakaryocytic differentiation of leukemic cell line, MC3, by phorbol ester : Induction of glycoprotein IIb/IIIa and effects on expression of IL-6, IL-6 receptor, mpl and GATA genes." Leukemia Res.(in press).

[Publications] Machida, T.: "Cochlioquinone A, an inhibitor of diacylglycerol kinase." J. Antibiotics. 48. 1076-1080 (1995)

[Publications] Monden, Y.: "Stimulation of the expression of rhoB contributes to the ability of azatyrosine to convert c-erbB-2-transformed cells to a normal morphology." Oncogene Reports. 3. 49-55 (1996)

[Publications] Monden, Y.: "Azatyrosine inhibits the activation of c-raf-1, c-jun and AP-1 but not the activation of ras during signal transduction triggered by oncogenic c-erb-2." Oncogene Reports. 3. 33-44 (1996)

[Publications] Mizutani, Y.: "Induction of erythroid differentiation in leukemic K562 cells by an S-adenosylhomocysteine hydrolase inhibitor, aristeromycin." Biochem. Biophys. Res. Commun.207. 69-74 (1995)

[Publications] Ui, H.: "Inhibition of phosphatidylinositol-specific phospholipase C activity by fluvirucin B2." J. Antibiotics. 48. 387-390 (1995)

[Publications] Imoto, M.: "In situ inhibition of protein-tyrosine phosphatase by dephostatin." Cell. Pharmacol.2. 199-203 (1995)

[Publications] Ui, H.: "A novel cyclic lipoundecapeptide, pholipeptin, isolated from Pseudomonas Sp." Tetrahedron Lett.36. 7479-7480 (1995)

[Publications] Sakai, T.: "Absolute configuration of spicamycin, an antitumor antibiotic produced by Streptomyces alanosinicus." J. Antibiotics. 48. 899-900 (1995)

[Publications] Hayakawa, Y.: "Anguinomycins C and D, new antitumor antibiotics with selective cytotoxicity against transformed cells." J. Antibiotics. 48. 954-961 (1995)

[Publications] Hayakawa, Y.: "Selective cytotoxicity of mycophenolic acid against transformed cells." J. Antibiotics. 48. 1182-1184 (1995)

[Publications] Shin-ya, K.: "Novel neuronal cell protecting substances, aestivophoenins A and B, produced by Streptomyces purpeofuscus." J. Antibiotics. 48. 1378-1381 (1995)

[Publications] Komiyama, K.: "Lousianins A, B, C and D : Non-steroidal growth inhibitors of testosterone SC 115 cells. I. Taxonomy, Fermentation, Isolation and Biological Characteristics." J. Antibiotics. 48. 1086-1089 (1995)

[Publications] Takamatsu, S.: "Lousianins A, B, C and D : non-steroidal growth inhibitors of testosterone SC 115 cells. II. Physico-chemical properties and structural elucidation." J. Antibiotics. 48. 1090-1094 (1995)

[Publications] Hayashi, M.: "Macrosphelide, a novel inhibitor of cell-cell adhesion molecule. I. Taxonomy, fermentation, isolation and biological activities." J. Antibiotics. 48. 1435-1439 (1995)

[Publications] Takamatsu, S.: "Macrosphelide, a novel inhibitor of cell-cell adhesion molecule. II. Physicochemical properties and structure elucidation." J. Antibiotics. 49. 95-98 (1996)

[Publications] Hayashi, M.: "Chlovalicin, a new cytocidal antibiotic produced by Sphorothrix sp. FO-4649. I. Taxonomy, fermentation, isolation and biological activities." J. Antibiotics. (in press).

[Publications] Takamatsu, S.: "Chlovalicin, a new cytocidal antibiotic produced by Sphorothrix sp. FO-4649. II. Physicochemical properties and structural elucidation." J. Antibiotics. (in press).

[Publications] Nakae, K.: "ERM, a PEA3 subfamily of Ets transcription factors, cancooperate with c-Jun." J. Biol. Chem.270. 23795-23800 (1995)

[Publications] Nakajima, K.: "Signal transduction through IL-6 receptor : involvement of multiple protein kinases, Stat factors and a novel H-7-sensitive pathway." Ann. New York Acad. Sci.762. 55-70 (1995)

[Publications] Hibi, M.: "IL-6 family cytokine and signal transduction : a model of the cytokine system." J. Mol. Med.(1996)

[Publications] Kojima, H.: "IL-6-inducible complexes on an IL-6 response element of the junB promoter contain Stat3 and 36 kDa CRE-like site binding protein(s)." Oncogene. (in press).

[Publications] Yamanaka, Y.: "Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation." EMBO J.(in press).

[Publications] Yoneda, J.: "Role of the heparin-binding domain of chimeric peptides derived from fibronectin in cell spreading and motility." Exp. Cell Res.217. 169-179 (1995)

[Publications] Sato, K.: "Inhibition of tumor-induced angiogenesis by a synthetic lipid A analogue with low toxicity, DT-5461." Jpn. J. Cancer Res.86. 374-382 (1995)

[Publications] Fujii, H.: "Human melanoma invasion and metastasis enhancement by high expression of aminopeptidase N/CD13." Clin. Expl. Metastasis. 13. 337-344 (1995)

[Publications] Sato, K.: "A novel synthetic lipid A analogue with low endotoxicity, DT-5461, prevents lethal endotoxemia." Infect. Immun.63. 2859-2866 (1995)

[Publications] Mochizuki, M.: "Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20 (R)- and 20 (S)-ginsenoside-Rg3, of Red ginseng." Biol. Pharm. Bull.18. 1197-1202 (1995)

[Publications] Komazawa, H.: "Combination of anti-cell adhesive synthetic Arg-Gly-Asp-Ser analogue and anti-cancer drugs heightens their original anti-metastatic activities." Oncology Res.7. 341-351 (1995)

[Publications] Fujii, H.: "Antimetastatic activities of synthetic RGDS or RLDS peptide analogues and their inhibitory mechanisms." Biol. Pharm. Bull.18. 1681-1688 (1995)

[Publications] Oikawa, T.: "Depudecin, a microbial metabolite containing two epoxide groups, exhibits anti-angiogenic activity in vivo." Chem. Pharm. Bull.18. 1305-1307 (1995)

[Publications] Inaba, M.: "Reduced activity of anabolizing enzymes in 5-fluorouracil-resistant human stomach cancer cells." Jpn. J. Cancer Res.(in press).

[Publications] Inaba, M.: "In vitro-in vivo correlation in anticancer drug sensitivity test using AUC-based concentrations and collagen gel droplet-embedded culture." Oncology. (in press).

[Publications] Yano, S.: "Differential effects of anti-inflammatory cytokines (IL-4, IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor (MCAF)." J. Leukocyte Biol.57. 303-309 (1995)

[Publications] Yano, S.: "Novel metastasis model of human lung cancer in NK-cell depleted SCID mice." Int. J. Cancer.(in press).

上原至雅国立予防衛生研究所, 生物活性物質部, 室長 (50160213)