天然物由来制癌物質の探索とその化学的誘導に関する研究

1989 Fiscal Year Annual Research Report

• Project/Area Number: 01010018
• Research Institution: The University of Tokyo
• Principal Investigator: 瀬戸 治男 東京大学, 応用微生物研究所, 教授 (10013335)
• Co-Investigator(Kenkyū-buntansha): 長田 裕之 理化学研究所, 研究員 (80160836) ; 長尾 善光 京都大学, 化学研究所, 助教授 (40027074) ; 岩崎 成夫 東京大学, 応用微生物研究所, 教授 (00013326) ; 別府 輝彦 東京大学, 農学部, 教授 (80011873) ; 大岳 望 帝京大学, 理工学部, 教授 (30013303)
• Keywords: lavanducyanin / gilvocarcin / leptomycin / 細胞周期特異的阻害剤 / rhizoxin / P-glycoprotein / エトポシド / epiderstatin

Research Abstract

本年度の各班員の研究実績は以下のとおりである。(瀬戸)低血清濃度で細胞の増殖を促進する物質を検索し、新放線菌の培養液から新規化合物lavanducyaninを単離しその構造を決定した。本化合物はphenazine系の化合物でP388に活性を示した。(大岳)抗腫瘍抗生物質であるgilvocarcinの化学修飾を行ない、血管形成阻害効果が親化合物に比較して著しく活性の増大している2種の誘導体を得た。(別府)細胞周期特異的物質の検索を行ない、数種の微生物が活性物質を生産することを見出しその精製を進めている。また、leptomycinが細胞周期特異的阻害剤であることを見出した。(岩崎)微小管の重合阻害剤であるrhizoxinの誘導体の調製を行ない、アシル誘導体が固形癌に対し極めてすぐれた治療効果を示すことを見出した。また微小管重合阻害剤の検索を行ない、数種の微生物の培養液から活性物質精製している。(鶴尾)制癌剤耐性細胞の耐性機構の解明を行ない、P-glycoproteinが重要な役割を果していることを証明した。またアンスラサイクリン抗生物質の誘導体であるMXー2、ME2303が耐性細胞に有効であることを証明した。(長尾)エトポシドの糖部分を不飽和脂肪酸で置換した化合物が強力な制癌作用を示した。また、エトポシドの糖部分の炭素の立体を反転させたものは親化合物より強力な作用を示した。(長田)上皮増殖因子の作用を阻害する物質として得たepiderstatinの構造を決定し、その詳細な作用機作を解明したG_0特異的阻害剤であることを明らかにした。(角川)ヒトパピローマウイルスによって悪性形質転換したNIH3T3細胞(T601細胞)を正常化する活性物質の検索を行ない、数種の粘液細菌の菌体から活性物質を精製している。(深沢)チロシンキナーゼの特異的阻害剤であるherbimycinの作用機作を研究し、その作用特異性が高く、p60^<v-sarc>に特異的に結合し、結合部位がシステイン残基であることを見出した。

Research Products

• [Publications] S.Imai: "Lavanducyanin,a new antitumor substance produced by Streptomyces sp." J.Antibiotics. 42. 1196-1198 (1989)
• [Publications] K.Shindo: "Thiazostatin A and thiazostatin B,new antioxidants produced by Streptomyces tolurosus." J.Antibiotics. 42. 1526-1529 (1989)
• [Publications] T.Kawano: "Isolation and structures of new chromomycin antibiotics 02-3D and 02-3G from Streptomyces avellaneus." J.Antibiotics. 43. 110-113 (1990)
• [Publications] K.Shin-ya: "Isolation of an antioxidative agent,naphterpin." J.Antibiotics. 43. (1990)
• [Publications] K.Shin-ya: "Isolation of a new antitumor substance,benthocyanin." in preparation.
• [Publications] K.Shin-ya: "Structure of a new antitumor substance,benthocyanin." in preparation.
• [Publications] S.Hiramoto: "Studies on a potentiator of the antitumor activity of bleomycin.I.Taxonomy of the producing organism,and production and biological activity of N 1478 substance." in preparation.
• [Publications] S.Hiramoto: "Studies on a potentiator of the antitumor activity of bleomycin.II.Structural studies on N 1478 substance." in preparation.
• [Publications] S.Nakajima: "A novel method for regio-and stereoselective hydroxylation of anthracycline glycosides." Tetranhedron Lett.30. 4857-4858 (1989)
• [Publications] M.Nakagawa: "Microbial conversion of anthracyclinones to carminomycins by a blocked mutant of Actinomadura roseoviolacea." J.Antibiotics. 42. 1698-1703 (1989)
• [Publications] M.Yoshida: "Structural specificity for biological activity of trichostatin A,specific inhibitor of mammalian cell cycle with potent differentiation-inducing activity in Friend leukemia cells." submitted.
• [Publications] M.Yoshida: "Effects of leptomycin B on the cell cycle of fibroblasts and fission yeast cells." Exp.Cell Res.(1990)
• [Publications] M.Takahashi: "Rhizoxin resistant mutants with an altered @-tubulin gene in Aspergillus nidulans." Mol.Gen.Genet.220. 53-59 (1989)
• [Publications] M.Takahashi: "Molecular basis for determining the sensitivity of eucaryotes to an antimitotic drug,rhizoxin." Mol.Gen.Genet.submitted.
• [Publications] A.S.Sullivan: "Interaction of rhizoxin with bovine brain tubulin." Cancer Res.submitted.
• [Publications] Y.Kato: "Synthesis,tubulin binding,cytotoxicity,and structure-activity relationship of rhizoxin derivatives:synthesis of a photoaffinity derivatives of rhizoxin." Chem.Pharm.Bull.in preparation.
• [Publications] T.Tsuruo: "Antitumor activity of ME2303,a fluorine-containing anthracycline,against human tumors implanted in nude mice." Jpn.J.Cancer Res.80. 686-689 (1989)
• [Publications] T.Tsuruo: "A fluorine-containing anthracycline(ME2303)as a new antitumor agent against murine and human tumors and their multidrug-resistant sublines." Cancer Res.49. 5537-5542 (1989)
• [Publications] Y.Nagao: "New general asymmetric synthesis of versatile g-alkylated butenolides and its application to expeditious synthesis of the chiral Geissman-Waiss lactones useful for(+)-retronecine synthesis." J.Org.Chem.54. 5211-5217 (1989)
• [Publications] Y.Nagao: "Biomimetic,chemical,and spectroscopic evaluations for the radiosensitizing potential of N1- and N2-substituted derivatives of 3-nitro-1,2,4-triazole toward hypoxic cells in the radiotherpy:Remarkably different substitution effect." Tetrahedron.
• [Publications] Y.Nagano: "New class of camptothecin derivatives as potential antitumor agents against P388 lymphocytic leukemia." J.Med.Chem.in preparation.
• [Publications] Y.Nagano: "Antitumor activity of novel podophyllotoxin fatty acid derivatives." J.Med.Chem.in preparation.
• [Publications] H.Osada: "A new biological role of .sangivamycin;Inhibition of protein kinases." J.Antibiotics. 42. 102-106 (1989)
• [Publications] J.Magae: "Comparison of the effect of tautomycin and phorbol ester on protein kinase C in a cell-free system." J.Antibiotics. 42. 1290-1293 (1989)
• [Publications] H.Osada: "Epiderstatin,A new inhibitor of the mitogenic activity induced by epidermal growth factor.I.Taxonomy,fermentation,isolation and characterization." J.Antibiotics. 42. 1599-1606 (1989)
• [Publications] T.Sonoda: "Epiderstatin,A new inhibitor of the mitogenic activity induced by epidermal growth factor,II.Structure elucidation." J.Antibiotics. 42. 1607-1609 (1989)
• [Publications] H.Osada: "A new ini abitor of protein kinase C,RK-286C(4'-demethyl-amino-4'-hydroxystaurosporine).I.Screening,taxonomy,fermentation and biological activity." J.Antibiotics. 43. (1990)
• [Publications] H.Takahashi: "A new inhibitor of protein kinase C,RK-286C(4'-demethylamino-4'-hydroxystaurosporine).II.Isolation,physico-chemical properties and structure." J.Antibiotics. 43. (1990)
• [Publications] T.Sonoda: "Epiderstatin and its related glutarimide antibiotics inhibit the cell growth induced by mitogen stimulation." Agric.Biol.Chem.
• [Publications] H.Osada: "Reversion of Rous sarcoma virus transformation by a novel antibiotic,epiderstatin." Cancer Res.
• [Publications] K.Tsutsumi: "In situ hybridization and immunohistochemical study of human papillomavirus infection in adult laryngeal papillomas." Laryngoscope. 99. 80-85 (1989)
• [Publications] J.Yokota: "Loss of heterozygosity on the short arm of chromosome 3 in carcinoma of the uterine cervix." Cancer Res.49. 3598-3601 (1989)
• [Publications] Y.Imai: "Purification and DNA-binding properties of human papillomavirus type 16 E6 protein expressed in Escherichia coli." Biochem.Biophys.Res.Commun.164. 1402-1410 (1989)
• [Publications] T.Ishibashi: "HPV DNA in squamous cell carcinoma of the upper aerodigestive tract." Arch.Otolaryngol.
• [Publications] T.Ishibashi: "Presence of human papillomavirus type 6-related sequences in inverted papilloma." Archives of Oto-Rhino-Laryngology.