1996 Fiscal Year Annual Research Report

がんの遺伝子異常に基づく新しい抗がん物質の探索

Research Project

Project/Area Number	08266113
Research Category	Grant-in-Aid for Scientific Research on Priority Areas
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)	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)
Keywords	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
Research Abstract	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。

Research Products

(33 results)

All Other

All Publications (33 results)

[Publications] 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)
[Publications] 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).
[Publications] Hori,H.: "Structure of angelmicin B,a novel src signal transduction inhibitor." Tetrahedron Lett.37. 2785-2788 (1996)
[Publications] 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)
[Publications] Shimizu,S.: "Involvement of hydrogen peroxide production in erbstatin-induced apoptosis in human small cell lung carcinoma cells." Cancer Research. 56. 4978-4982 (1996)
[Publications] Deguchi,A.: "Inhibition of G1 cyclin expression in normal rat kidney cells by inostamycin,a phosphatidylinositol synthesis inhibitor." J.Biochem.120. 1118-1122 (1996)
[Publications] Sanpei,K.: "Synthesis of ribofuranosyl glycosides of echiguanines A and B,inhibitors of phosphatidylinositol 4-kinase." Bioorganic & Medicinal Chemistry Letters. 6. 2487-2490 (1996)
[Publications] Kunigami,T.: "A neuronal cell protecting substance,4-demethoxymichigazone,produced by Streptomyces halstedii." J.Antibiot.49. 312-313 (1996)
[Publications] 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)
[Publications] Hayakawa,Y.: "Structure of a new microbial metabolite,neuchromenin." Tetrahedron Lett.37. 6363-6364 (1996)
[Publications] 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)
[Publications] 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)
[Publications] Nose,K.: "Functional activation of the egr-1 (early growth response-1) gene by hydrogen peroxide." Biochem.J.316. 381-383 (1996)
[Publications] 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)
[Publications] 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)
[Publications] 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).
[Publications] 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).
[Publications] 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).
[Publications] 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)
[Publications] Takamatsu,S.: "A new inhibitor of melanogenesis,albocycline K3,produced by Streptomyces sp.OH-3984" J.Antibiotics. 49. 485-486 (1996)
[Publications] 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)
[Publications] 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)
[Publications] Takamatsu,S.: "Macrosphelide,a novel inhibitor of cell-cell adhesion molecule.II.Physicochemical properties and structure elusidation." J.Antibiotics. 49. 95-98 (1996)
[Publications] 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)
[Publications] Sato,K.: "Tolerance to the anti-metastatic effect of lipopolysaccharide against liver metastasis of tumor in mice." Int.J.Cancer. 66. 98-103 (1996)
[Publications] 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)
[Publications] Oku,N.: "Liposomal Arg-Gly-Asp analogs effectively inhibit metastatic B16 melanoma colonization in murine lungs." Life Science. 58(24). 2263-2270 (1996)
[Publications] 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)
[Publications] Nishimura,T.: "Application of interleukin 12 to antitumor cytokine and gene therapy." Cancer Chemother.Pharmacol.38. 27-34 (1996)
[Publications] 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)
[Publications] 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)
[Publications] Ono,M.: "Inhibition of tumor growth and neovascularization by an antigasric ulcer agent,irsogladine." Cancer Res.56. 1512-1516 (1996)
[Publications] 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 Fiscal Year Annual Research Report

がんの遺伝子異常に基づく新しい抗がん物質の探索

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.: "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)

[Publications] 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).

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

[Publications] 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)

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

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

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

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

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

[Publications] 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).

[Publications] 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).

[Publications] 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).

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

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

[Publications] 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)

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

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

上原至雅国立予防衛生研究所, 生物活性物質部, 室長 (50160213)