1996 年度実績報告書

がんの遺伝子異常に基づく新しい抗がん物質の探索

研究課題

研究課題/領域番号	08266113
研究種目	重点領域研究
研究機関	国立予防衛生研究所
研究代表者	上原至雅国立予防衛生研究所, 生物活性物質部, 室長 (50160213)
研究分担者	済木育夫富山医科薬科大学, 和漢薬研, 教授 (80133776) 小宮山寛機 (社)北里研究所, 基礎研, 副所長 (00106676) 野瀬清昭和大学, 薬学部, 教授 (70012747) 早川洋一東京大学, 分子細胞生物研, 助教授 (20208606) 井本正哉慶應義塾大学, 理工学部, 助教授 (60213253)
キーワード	がん化シグナル / 細胞周期 / チロシンキナーゼ阻害剤 / アポトーシス / マクロライド / がん転移 / 転写因子 / 接着
研究概要	1.がん化シグナル抑制物質を探索して新規ペプチド性化合物(NA22598)を単離し、本物質がcyclin D1およびcdk4の発現を減少させ細胞周期をG_1期に停止させることを明らかにした。また、hibarimicinと命名した一群の新規チロシンキナーゼ阻害剤を単離し分子構造を決定した。さらに、チロシンキナーゼ阻害剤が細胞内過酸化水素の上昇を引き起こし、ヒト肺小細胞癌のアポトーシスを誘導することを見いだした。 2.Rb蛋白質不活化細胞を選択的にアポトーシス誘導する物質を探索し、新規の20員環マクロライドapoptolidinを単離した。また、WAF1/p21遺伝子エンハンサーを用い、変異型p53蛋白質の機能を回復させる物質の検索系を確立した。 3.血管内皮細胞と癌細胞の接着を阻害する物質を探索して、新規マクロライドmacrosphelide A,Bを単離した。これらの物質は接着分子sLe^xに作用し、マウス肺転移モデルにおいて優れた転移抑制効果を示した。また、がん細胞の基底膜への浸潤を抑制する物質を漢方薬中に探索し、五倍子の一成分galloyl-glucose:GG6-10が強い浸潤抑制効果を示すことを明らかにした。 4.転写因子ets-1の血管新生における役割を明らかにし、血管新生抑制作用をもついくつかの物質がets-1の発現を抑制することを見いだした。

研究成果

(33件)

すべてその他

すべて文献書誌 (33件)

[文献書誌] Fukazawa,H.: "Inhibitors of anchorage-independent growth affect the growth of transformed cells on poly (2-hydroxyethyl methacrylate) -coated surfaces." Int.J.Cancer. 67. 876-882 (1996)
[文献書誌] Kawada,M.: "Inhibiton of ancharage-independent growth of ras-transformed cells on polyHEMA surface by antisense oligonucleotides directed against K-ras." Biochem.Biophys.Res.Commun.(in press).
[文献書誌] Hori,H.: "Structure of angelmicin B,a novel src signal transduction inhibitor." Tetrahedron Lett.37. 2785-2788 (1996)
[文献書誌] Yokoyama,A.: "Angelmicin B,a new inhibitor of oncogenic signal transduction,inhibits growth and induces myelomonocytic differentiation of human myeloid leukemia HL-60 cells." Leukemia Res.20. 491-497 (1996)
[文献書誌] Shimizu,S.: "Involvement of hydrogen peroxide production in erbstatin-induced apoptosis in human small cell lung carcinoma cells." Cancer Research. 56. 4978-4982 (1996)
[文献書誌] Deguchi,A.: "Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin,a phosphatidylinositol synthesis inhibitor." J.Biochem.120. 1118-1122 (1996)
[文献書誌] Sanpei,K.: "Synthesis of ribofuranosyl glycosides of echiguanines A and B,inhibitors of phosphatidylinositol 4-kinase." Bioorganic & Medicinal Chemistry Letters. 6. 2487-2490 (1996)
[文献書誌] Kunigami,T.: "A neuronal cell protecting substance,4-demethoxymichigazone,produced by Streptomyces halstedii." J.Antibiot.49. 312-313 (1996)
[文献書誌] Ohkura,M.: "Characteristics of ^<45>Ca^<2+> release induced by quinolidomicin A_1,a 60-membered macrolide fron skeletal muscle sarcoplasmic reticulum." Biochim.Biophys.Acta. 1294. 177-182 (1996)
[文献書誌] Hayakawa,Y.: "Structure of a new microbial metabolite,neuchromenin." Tetrahedron Lett.37. 6363-6364 (1996)
[文献書誌] Hayakawa,Y.: "Studies on new antitumor antibiotics,leptofuranins A,B,C and D.I.Taxonomy,fermentation,isolation and biological activities." J.Antibiot.49. 974-979 (1996)
[文献書誌] Hayakawa,Y.: "Studies on new antitumor antibiotics,leptofuranins A,B,C and D.II.Physicochemical properties and structure elucidation." J.Antibiot.49. 980-984 (1996)
[文献書誌] Nose,K.: "Functional activation of the egr-1 (early growth response-1) gene by hydrogen peroxide." Biochem.J.316. 381-383 (1996)
[文献書誌] Arata,S.: "Inhibition of NIH3T3 cells by the expression of the small molecular weight heat shock protein HSP27 : Involvement of its phosphorylation and aggregation at the C-terminal region." J.Cell.Physiol.170. 19-26 (1997)
[文献書誌] Patel,K.: "Cloning and early dorsal axial expression of Flik,a chicken follistatin-related gene : Evidence for involvement in dorsalization.neural induction." Develop.Biol.178. 327-342 (1996)
[文献書誌] Shibanuma,M.: "Induction of senescence-like phonotypes by the forced expression of hic-5 encoding a novel LIM motif protein in immortalized human fibroblasts." Mol.Cell.Biol.(in press).
[文献書誌] Murata,M.: "Involvement of reactive oxygen species in the induction of chemokine JE/MCP-1 gene by phorbol-12-myristate-13-acetate in Balb 3T3 cells." Cell Struct.& Function. (in press).
[文献書誌] Mashimo,J.: "Decrease in the expression of a novel TGF b1-inducible and ras-recision gene,TSC-36,in human cancer cells." Cancer Lett.(in press).
[文献書誌] Hayashi,M.: "Madindoline,a novel inhibitor of IL-6 activity from Streptomyces sp.K93-0711.I.Taxonomy,Fermentation,Isolation and Biological Activities." J.Antibiotics. 49. 1091-1095 (1996)
[文献書誌] Takamatsu,S.: "A new inhibitor of melanogenesis,albocycline K3,produced by Streptomyces sp.OH-3984" J.Antibiotics. 49. 485-486 (1996)
[文献書誌] Hayashi,M.: "Chlovalicin,a new cytocidal antibiotic produced by Sphorothrix sp.FO-4649.I.Taxonomy,fermentation,isolation and biological activities." J.Antibiotics. 49. 631-634 (1996)
[文献書誌] Takamatsu,S.: "Chlovalicin,a new cytocidal antibiotic produced by Sphorothrix sp.FO-4649.II.Physicochemical properties and structural elucidation." J.Antibiotics. 49. 635-638 (1996)
[文献書誌] Takamatsu,S.: "Macrosphelide,a novel inhibitor of cell-cell adhesion molecule.II.Physicochemical properties and structure elusidation." J.Antibiotics. 49. 95-98 (1996)
[文献書誌] Saiki,I.: "Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor cell arrest in lungs followed by extravasation." Int.J.Cancer. 65. 833-839 (1996)
[文献書誌] Sato,K.: "Tolerance to the anti-metastatic effect of lipopolysaccharide against liver metastasis of tumor in mice." Int.J.Cancer. 66. 98-103 (1996)
[文献書誌] Fujii,H.: "Vaccination of tumor cells transfected with B7-1 (CD80) gene induces the anti-metastatic effect and tumor immunity in mice." Int.J.Cancer. 66. 219-227 (1996)
[文献書誌] Oku,N.: "Liposomal Arg-Gly-Asp analogs effectively inhibit metastatic B16 melanoma colonization in murine lungs." Life Science. 58(24). 2263-2270 (1996)
[文献書誌] Ohnishi,Y.: "Inhibitory effect of a traditional Chinese medicine,Juzen-taiho-to on progressive growth of weakly malignant colne cells derived from murine fibrosarcoma." Jpn.J.Cancer Res.87. 1039-1044 (1996)
[文献書誌] Nishimura,T.: "Application of interleukin 12 to antitumor cytokine and gene therapy." Cancer Chemother.Pharmacol.38. 27-34 (1996)
[文献書誌] Nishikawa,N.: "Synthesis and biological properties of partially modified retro and retro-inverso pseudo peptides of Arg-Gly-Asp (RGD)." Bioorg.Med.Chem.Lett.6(22). 2725-2728 (1996)
[文献書誌] Fujii,H.: "Inhibition of tumor invasion and metastasis by peptidic mimetics of Arg-Gly-Asp (RGD) derived from the cell recognition site of fibronectin." Oncology Res.56. 1512-1516 (1996)
[文献書誌] Ono,M.: "Inhibition of tumor growth and neovascularization by an antigasric ulcer agent,irsogladine." Cancer Res.56. 1512-1516 (1996)
[文献書誌] Iwasaka,C.: "Ets-1 regualtes angiogenesis by inducing the expression of urokinase-type plasminogen actiavtor and matrix metalloproteinase-1 and the migration of vascular endothelial cells." J.Cell.Physiol.169. 522-531 (1996)

1996 年度 実績報告書

がんの遺伝子異常に基づく新しい抗がん物質の探索

研究代表者

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

研究成果

[文献書誌] Fukazawa,H.: "Inhibitors of anchorage-independent growth affect the growth of transformed cells on poly (2-hydroxyethyl methacrylate) -coated surfaces." Int.J.Cancer. 67. 876-882 (1996)

[文献書誌] Kawada,M.: "Inhibiton of ancharage-independent growth of ras-transformed cells on polyHEMA surface by antisense oligonucleotides directed against K-ras." Biochem.Biophys.Res.Commun.(in press).

[文献書誌] Hori,H.: "Structure of angelmicin B,a novel src signal transduction inhibitor." Tetrahedron Lett.37. 2785-2788 (1996)

[文献書誌] Yokoyama,A.: "Angelmicin B,a new inhibitor of oncogenic signal transduction,inhibits growth and induces myelomonocytic differentiation of human myeloid leukemia HL-60 cells." Leukemia Res.20. 491-497 (1996)

[文献書誌] Shimizu,S.: "Involvement of hydrogen peroxide production in erbstatin-induced apoptosis in human small cell lung carcinoma cells." Cancer Research. 56. 4978-4982 (1996)

[文献書誌] Deguchi,A.: "Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin,a phosphatidylinositol synthesis inhibitor." J.Biochem.120. 1118-1122 (1996)

[文献書誌] Sanpei,K.: "Synthesis of ribofuranosyl glycosides of echiguanines A and B,inhibitors of phosphatidylinositol 4-kinase." Bioorganic & Medicinal Chemistry Letters. 6. 2487-2490 (1996)

[文献書誌] Kunigami,T.: "A neuronal cell protecting substance,4-demethoxymichigazone,produced by Streptomyces halstedii." J.Antibiot.49. 312-313 (1996)

[文献書誌] Ohkura,M.: "Characteristics of ^<45>Ca^<2+> release induced by quinolidomicin A_1,a 60-membered macrolide fron skeletal muscle sarcoplasmic reticulum." Biochim.Biophys.Acta. 1294. 177-182 (1996)

[文献書誌] Hayakawa,Y.: "Structure of a new microbial metabolite,neuchromenin." Tetrahedron Lett.37. 6363-6364 (1996)

[文献書誌] Hayakawa,Y.: "Studies on new antitumor antibiotics,leptofuranins A,B,C and D.I.Taxonomy,fermentation,isolation and biological activities." J.Antibiot.49. 974-979 (1996)

[文献書誌] Hayakawa,Y.: "Studies on new antitumor antibiotics,leptofuranins A,B,C and D.II.Physicochemical properties and structure elucidation." J.Antibiot.49. 980-984 (1996)

[文献書誌] Nose,K.: "Functional activation of the egr-1 (early growth response-1) gene by hydrogen peroxide." Biochem.J.316. 381-383 (1996)

[文献書誌] Arata,S.: "Inhibition of NIH3T3 cells by the expression of the small molecular weight heat shock protein HSP27 : Involvement of its phosphorylation and aggregation at the C-terminal region." J.Cell.Physiol.170. 19-26 (1997)

[文献書誌] Patel,K.: "Cloning and early dorsal axial expression of Flik,a chicken follistatin-related gene : Evidence for involvement in dorsalization.neural induction." Develop.Biol.178. 327-342 (1996)

[文献書誌] Shibanuma,M.: "Induction of senescence-like phonotypes by the forced expression of hic-5 encoding a novel LIM motif protein in immortalized human fibroblasts." Mol.Cell.Biol.(in press).

[文献書誌] Murata,M.: "Involvement of reactive oxygen species in the induction of chemokine JE/MCP-1 gene by phorbol-12-myristate-13-acetate in Balb 3T3 cells." Cell Struct.& Function. (in press).

[文献書誌] Mashimo,J.: "Decrease in the expression of a novel TGF b1-inducible and ras-recision gene,TSC-36,in human cancer cells." Cancer Lett.(in press).

[文献書誌] Hayashi,M.: "Madindoline,a novel inhibitor of IL-6 activity from Streptomyces sp.K93-0711.I.Taxonomy,Fermentation,Isolation and Biological Activities." J.Antibiotics. 49. 1091-1095 (1996)

[文献書誌] Takamatsu,S.: "A new inhibitor of melanogenesis,albocycline K3,produced by Streptomyces sp.OH-3984" J.Antibiotics. 49. 485-486 (1996)

[文献書誌] Hayashi,M.: "Chlovalicin,a new cytocidal antibiotic produced by Sphorothrix sp.FO-4649.I.Taxonomy,fermentation,isolation and biological activities." J.Antibiotics. 49. 631-634 (1996)

[文献書誌] Takamatsu,S.: "Chlovalicin,a new cytocidal antibiotic produced by Sphorothrix sp.FO-4649.II.Physicochemical properties and structural elucidation." J.Antibiotics. 49. 635-638 (1996)

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

[文献書誌] Saiki,I.: "Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor cell arrest in lungs followed by extravasation." Int.J.Cancer. 65. 833-839 (1996)

[文献書誌] Sato,K.: "Tolerance to the anti-metastatic effect of lipopolysaccharide against liver metastasis of tumor in mice." Int.J.Cancer. 66. 98-103 (1996)

[文献書誌] Fujii,H.: "Vaccination of tumor cells transfected with B7-1 (CD80) gene induces the anti-metastatic effect and tumor immunity in mice." Int.J.Cancer. 66. 219-227 (1996)

[文献書誌] Oku,N.: "Liposomal Arg-Gly-Asp analogs effectively inhibit metastatic B16 melanoma colonization in murine lungs." Life Science. 58(24). 2263-2270 (1996)

[文献書誌] Ohnishi,Y.: "Inhibitory effect of a traditional Chinese medicine,Juzen-taiho-to on progressive growth of weakly malignant colne cells derived from murine fibrosarcoma." Jpn.J.Cancer Res.87. 1039-1044 (1996)

[文献書誌] Nishimura,T.: "Application of interleukin 12 to antitumor cytokine and gene therapy." Cancer Chemother.Pharmacol.38. 27-34 (1996)

[文献書誌] Nishikawa,N.: "Synthesis and biological properties of partially modified retro and retro-inverso pseudo peptides of Arg-Gly-Asp (RGD)." Bioorg.Med.Chem.Lett.6(22). 2725-2728 (1996)

[文献書誌] Fujii,H.: "Inhibition of tumor invasion and metastasis by peptidic mimetics of Arg-Gly-Asp (RGD) derived from the cell recognition site of fibronectin." Oncology Res.56. 1512-1516 (1996)

[文献書誌] Ono,M.: "Inhibition of tumor growth and neovascularization by an antigasric ulcer agent,irsogladine." Cancer Res.56. 1512-1516 (1996)

[文献書誌] Iwasaka,C.: "Ets-1 regualtes angiogenesis by inducing the expression of urokinase-type plasminogen actiavtor and matrix metalloproteinase-1 and the migration of vascular endothelial cells." J.Cell.Physiol.169. 522-531 (1996)

1996 年度実績報告書

上原至雅国立予防衛生研究所, 生物活性物質部, 室長 (50160213)