1992 年度実績報告書

新規構造を有する天然物由来抗癌物質に関する研究

研究課題

研究課題/領域番号	04151016
研究機関	東京大学
研究代表者	瀬戸治男東京大学, 応用微生物研究所, 教授 (10013335)
研究分担者	吉田稔東京大学, 農学部, 助手 (80191617) 馬替純二東工大学, 生命理工学部, 講師 (60199643) 長田裕之理化学研究所, 主任研究員 (80160836) 長尾善光徳島大学, 薬学部, 教授 (40027074) 岩崎成夫東京大学, 応用微生物研究所, 教授 (00013326)
キーワード	JS49 / ustiloxin A / reveromycin / radicicol / gilvocarcinの化学変換 / roseophilin / 多剤耐性克服 / 抗ガン物質
研究概要	本年度の各班員の研究実績は以下のとおりである。(瀬戸)ハピローマウイルスでトランスフォームしたNIH3T3細胞を正常化させる物質を検索し,放線菌の培養液から新規化合物であるJS49を単離し、その構造を決定した。また放線菌の培養液から強い細胞障害性を示す新規マクロライドを単離した。(岩崎)イネ病稲こうじより単離したustiloxin Aの構造を確定し、13員環構造を含む環状ペプチドであることを明らかにした。本化合物は既知化合物中、最強のチューブリン重合阻害活性を示した。(長田)reveromycin Aのラベル体を作成し、予備的検討により真核細胞の細胞質にreveromycinAと結合する蛋白質が存在することを示した。(吉田)フローサイトメーターによる細胞DNA含量の直接定量を用いた検索の結果、トランスフォームした細胞の細胞周期をG1、G2期で停止させるとともにその形態を正常化させる物質としてradicicolを再発見した。(馬替)脾臓細胞の幼若化反応を用いた探索系においてT細胞の幼若化を特異的に抑制する物質としてleucanicidinを同定した。またroseophilinがConAとの相乗効果を示し、細胞内小器官の酸性化を阻害することを見いだした。(長尾)campthotecinの誘導体を合成し、P388担癌マウスでの延命効果を検討したところ、ジヒドロキシクロトン酸エステルに抗癌活性が認められた。(柿沼)gilvocar Vから誘導したヒドロキシメチルギルボカルシンテトラアセタートを用いて、グリコシル体を調製した。(内藤)動植物細胞から酵母に至るまですべての細胞に存在するユビキチン系における作用点は、cisplatinとaclarubisinとでは異なり、cisplatinはタンパク質へのユビキチンの結合過程を阻害し、一方aclarubicinはユビキチン化タンパク質の分解過程を阻害することが明らかになった。

研究成果

(24件)

すべてその他

すべて文献書誌 (24件)

[文献書誌] Y.Hayakawa: "Structure of a new antibiotic,roseophilin." Tetrahedron Lett.33. 2701-2704 (1992)
[文献書誌] M.Nakagawa: "Studies on viridenomycin,a novel 24-membered macrocyclic lactam antibiotic." J.Antibiotics. 45. 1133-1138 (1992)
[文献書誌] S.Imai: "Exfoliazone and lavanducyanin,Potent growth promoting substances of rat liver cell line,RLN-8,produced by Streptomyces exfoliatusand Streptomyces aeriouvifer." J.Antibiotics. 46. (1993)
[文献書誌] S.Imai: "Resorcinin,a mammalian cell growth stimulating substance produced by Cytophaga Johnsonae." J.Antibiotics. 46. (1993)
[文献書誌] M.Nakai: "Studies on a microbial metabolite,trichostatin D,inducing morphological reversion of transformed cells." J.Antibiotics. 46. (1993)
[文献書誌] Y.Li: "Interaction of phomopsin a with porcine brain tubulin.Inhibition of tubulin polymerzation and binding at a rhizoxin binding site." Biochem.Pharmacol.43. 219-224 (1992)
[文献書誌] Y.Koiso: "Ustiloxin:A phytotoxin and mycotoxin from false smut balls on rice panicles." Tetrahedron Lett.33. 4157-4160 (1992)
[文献書誌] Y.Li: "Binding selectivity of rhizoxin,phomopsin A,vinblastinen,and ansamitocin P-3 to fungal tubulin:differential interactions of these antibiotic agents with brain and fungal tubulins." Biochem.Biophys.Res.Commun.187. 722-729 (1992)
[文献書誌] T.Sawada: "Identification of the fragment photoaffinity-labeled with azidodansyl-rhizoxin as Met-363 Lys-379 on tubulin." Biochem.Pharmacol.(1993)
[文献書誌] H.Osada: "Epiderstatin induces the flat reversion of NRK cells transformed by temperature-sensitive Rouse sarcoma virus." Biosci.Biotech.Biochem.56. 1801-1806 (1992)
[文献書誌] H.Takahashi: "Reveromycins,new inhibitors of eukaryotic cell growth.I.Producing organism,fermentation,isolation and physico-chemical properties." J.Antibiotics. 45. 1409-1413 (1992)
[文献書誌] H.Takahashi: "Reveromycins,new inhibitors of eukaryotic cell growth.II.Biological activities." J.Antibiotics. 45. 1414-1419 (1992)
[文献書誌] H.Koshino: "Reveromycins,new inhibitors of eukaryotic cell growth.III.Structures." J.Antibiotics. 45. 1420-1427 (1992)
[文献書誌] H.Sasaki: "Leptomycin B-induced fixation of X-ray-related potentially lethal damage." Radiat.Res.129. 163-170 (1992)
[文献書誌] K.Nishi: "A leptomycin B resistance gene of Schizosaccharomyces pombe encodes a protein similar to the mammalian P-glycoproteins." Mol.Microbiol.6. 761-769 (1992)
[文献書誌] H.J.Kwon: "Radicicol,an agent inducing the reversal of transforned phenotypes of src-transformed fibrodlasts." Biosci.Biotech.Biochem.56. 538-539 (1992)
[文献書誌] H.J.Kwon: "Potent and specific inhibition of p60v-src protein kinase both in vivo and in vitro by radicicol." Cancer Res.52. 6926-6930 (1992)
[文献書誌] K.Abe: "Leptolstatin from <Streptomyces>___- sp.SAM1595,a new gap phase-specific inhibitor of the mammalian cell cycle.I.Screening,taxonomy,purification and biological activities." J.Antibiotics. 46. (1993)
[文献書誌] T.Kataoka: "Effects of prodigiosin 25-C on cultured cell lines:its similarity to monovalent polyether ionophores and vacuolar type H^+-ATPase inhibitors." J.Antibiotics. 45. 1618-1625 (1992)
[文献書誌] J.Magae: "Effect of microbial products on glucose consumption and morphology of macrophages." Biosci.Biotech.Biochem.(1993)
[文献書誌] M.Naito: "Reversal of multidrug resistance by an immunosuppressive agent FK-506." Cancer Chemother.Pharmacol.29. 195-200 (1992)
[文献書誌] T.Isoe: "Inhibition of different steps of the ubiquitin system by cisplatin and aclarubucin." Biochim.Biophys.Acta. 1117. 131-135 (1992)
[文献書誌] M.Naito: "Functionally active homodimer of P-glycoprotein in multidrug-resistant tumor cells." Biochem.Biophys.Res.Commun.185. 284-290 (1992)
[文献書誌] T.Tatsuta: "Functional involvement of P-glycoprotein in blood-brain barrier." J.Biol.Chem.267. 20383-20391 (1992)

1992 年度 実績報告書

新規構造を有する天然物由来抗癌物質に関する研究

研究代表者

瀬戸 治男 東京大学, 応用微生物研究所, 教授 (10013335)

研究成果

[文献書誌] Y.Hayakawa: "Structure of a new antibiotic,roseophilin." Tetrahedron Lett.33. 2701-2704 (1992)

[文献書誌] M.Nakagawa: "Studies on viridenomycin,a novel 24-membered macrocyclic lactam antibiotic." J.Antibiotics. 45. 1133-1138 (1992)

[文献書誌] S.Imai: "Exfoliazone and lavanducyanin,Potent growth promoting substances of rat liver cell line,RLN-8,produced by Streptomyces exfoliatusand Streptomyces aeriouvifer." J.Antibiotics. 46. (1993)

[文献書誌] S.Imai: "Resorcinin,a mammalian cell growth stimulating substance produced by Cytophaga Johnsonae." J.Antibiotics. 46. (1993)

[文献書誌] M.Nakai: "Studies on a microbial metabolite,trichostatin D,inducing morphological reversion of transformed cells." J.Antibiotics. 46. (1993)

[文献書誌] Y.Li: "Interaction of phomopsin a with porcine brain tubulin.Inhibition of tubulin polymerzation and binding at a rhizoxin binding site." Biochem.Pharmacol.43. 219-224 (1992)

[文献書誌] Y.Koiso: "Ustiloxin:A phytotoxin and mycotoxin from false smut balls on rice panicles." Tetrahedron Lett.33. 4157-4160 (1992)

[文献書誌] Y.Li: "Binding selectivity of rhizoxin,phomopsin A,vinblastinen,and ansamitocin P-3 to fungal tubulin:differential interactions of these antibiotic agents with brain and fungal tubulins." Biochem.Biophys.Res.Commun.187. 722-729 (1992)

[文献書誌] T.Sawada: "Identification of the fragment photoaffinity-labeled with azidodansyl-rhizoxin as Met-363 Lys-379 on tubulin." Biochem.Pharmacol.(1993)

[文献書誌] H.Osada: "Epiderstatin induces the flat reversion of NRK cells transformed by temperature-sensitive Rouse sarcoma virus." Biosci.Biotech.Biochem.56. 1801-1806 (1992)

[文献書誌] H.Takahashi: "Reveromycins,new inhibitors of eukaryotic cell growth.I.Producing organism,fermentation,isolation and physico-chemical properties." J.Antibiotics. 45. 1409-1413 (1992)

[文献書誌] H.Takahashi: "Reveromycins,new inhibitors of eukaryotic cell growth.II.Biological activities." J.Antibiotics. 45. 1414-1419 (1992)

[文献書誌] H.Koshino: "Reveromycins,new inhibitors of eukaryotic cell growth.III.Structures." J.Antibiotics. 45. 1420-1427 (1992)

[文献書誌] H.Sasaki: "Leptomycin B-induced fixation of X-ray-related potentially lethal damage." Radiat.Res.129. 163-170 (1992)

[文献書誌] K.Nishi: "A leptomycin B resistance gene of Schizosaccharomyces pombe encodes a protein similar to the mammalian P-glycoproteins." Mol.Microbiol.6. 761-769 (1992)

[文献書誌] H.J.Kwon: "Radicicol,an agent inducing the reversal of transforned phenotypes of src-transformed fibrodlasts." Biosci.Biotech.Biochem.56. 538-539 (1992)

[文献書誌] H.J.Kwon: "Potent and specific inhibition of p60v-src protein kinase both in vivo and in vitro by radicicol." Cancer Res.52. 6926-6930 (1992)

[文献書誌] K.Abe: "Leptolstatin from <Streptomyces>___- sp.SAM1595,a new gap phase-specific inhibitor of the mammalian cell cycle.I.Screening,taxonomy,purification and biological activities." J.Antibiotics. 46. (1993)

[文献書誌] T.Kataoka: "Effects of prodigiosin 25-C on cultured cell lines:its similarity to monovalent polyether ionophores and vacuolar type H^+-ATPase inhibitors." J.Antibiotics. 45. 1618-1625 (1992)

[文献書誌] J.Magae: "Effect of microbial products on glucose consumption and morphology of macrophages." Biosci.Biotech.Biochem.(1993)

[文献書誌] M.Naito: "Reversal of multidrug resistance by an immunosuppressive agent FK-506." Cancer Chemother.Pharmacol.29. 195-200 (1992)

[文献書誌] T.Isoe: "Inhibition of different steps of the ubiquitin system by cisplatin and aclarubucin." Biochim.Biophys.Acta. 1117. 131-135 (1992)

[文献書誌] M.Naito: "Functionally active homodimer of P-glycoprotein in multidrug-resistant tumor cells." Biochem.Biophys.Res.Commun.185. 284-290 (1992)

[文献書誌] T.Tatsuta: "Functional involvement of P-glycoprotein in blood-brain barrier." J.Biol.Chem.267. 20383-20391 (1992)

1992 年度実績報告書

瀬戸治男東京大学, 応用微生物研究所, 教授 (10013335)