がんの遺伝子異常に基づく新しい抗がん物質の探索

1998 Fiscal Year Annual Research Report

• Project/Area Number: 08266113
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: 上原 至雅 国立感染症研究所, 生物活性物質部, 室長 (50160213)
• Co-Investigator(Kenkyū-buntansha): 野瀬 清 昭和大学, 薬学部, 教授 (70012747) ; 早川 洋一 東京大学, 分子細胞生物学研究所, 助教授 (20208606) ; 内藤 幹彦 東京大学, 分子細胞生物学研究所, 助教授 (00198011) ; 井本 正哉 慶応大学, 理工学部, 助教授 (60213253) ; 沖 俊一 玉川大学, 学術研究所, 教授 (40264676)
• Keywords: Srcチロシンキナーゼ / Ablチロシンキナーゼ / アポトーシス / 細胞接着 / 血管新生 / RB / p21^<waf1> / 転移

Research Abstract

1. 1a-docosahexaenoyl mitomycin C、hibarimicin同族体(Srcチロシンキナーゼ阻害)、1577-33C(アポトーシス抑制)、apoxinl、adenopeptin(アポトーシス誘導)、macrosphelide誘導体(細胞接着阻害)AC7700(抗血管新生物質)等の新規物質を見出した。
2. Ablチロンンキナーゼ阻害剤CGP57148の作用を検討し、慢性骨髄性白血病K562細胞選択的にcaspaseを活性化し、アポトーシスを誘導することを明らかにした。
3. adenopeptinがRB不活化細胞選択的にアポトーシスを誘導することを明らかにし、抗菌物質nybomycinにp21^<Waf1>誘導の新しい生物活性を見出した。
4. melanoma肺転移モデルにおいてmacrosphelide Bに優れた抗転移活性を見出した。
5. AC7700はラットにおいて正常部位の血流には影響を与えることなく、腫瘍部位の血流を完全に遮断し、腫瘍の発育を著明に抑制した。

Research Products

• [Publications] Kawada,M.: "Up-regulation of p27Kip1 correlates inversely with anchorage-independent growth of human cancer cell lines." Jpn.J.Cancer Res.89. 110-115 (1998)
• [Publications] Shikano,M.: "1a docosahexaenoyl mitomycin C: a novel inhibitor of protein tyrosine kinase." Biochem.Biophys.Res.Commun.248. 858-863 (1998)
• [Publications] Leen,J.: "Inhibitory effects of 5-S-GAD on phosphorylation of v-Src and Bcr-abl tyrosine kinase." Biol.Pharm.Bull.21. 784-785 (1998)
• [Publications] Murakami,Y.: "Effect of herbimycin A on tyrosine kinase receptors and platelet derived growth factor(PDGF)-induced signal transduction." Biol.Pharm.Bull.21. 1030-1035 (1998)
• [Publications] Sasaki,S.: "Design of new inhibitors for cdc2 kinase based on a multiple pseudosubstrate structure." Bioorg.& Med.Chem.Lett.8. 1019-1022 (1998)
• [Publications] Shikano,M.: "Inhibition on protein tyrosine kinase activity by 1a-docosahexaenoyl mitomycin C. Annals of New York Academy of Sciences,Anticancer proteins and drugs: structure,function and design." Annals of New York Academy of Sciences. (in press). (1998)
• [Publications] Kawada,M.: "NA22598,a novel antitumor compound,reduces cyclin D1 levels,arrests cell cycle at G1 phase,and inhibits anchorage-independent growth of human tumor cells." Exp Cell Res.(in press). (1998)
• [Publications] Kajiura,T.: "Signal transduction inhibitors,hibarimicins A,B,C,D and G produced by Microbispora.I.Taxonomy,fermentation,isolation and physico-chemical and biological properties." J.Antiobiotics. 51. 394-401 (1998)
• [Publications] Hori,H.: "Signal transduction inhibitors,hibarimicins A,B,C,D and G produced by Microbispora.II.Structural studies." J.Antiobiotics. 51. 402-417 (1998)
• [Publications] S.Simizu,K.: "Induction of hydrogen peroxide production and Bax expression by CPP32(-like)proteases in tyrosine kinase inhibitor-induced apoptosis in human small cell lung carcinoma cells." Exp.Cell Res.238. 197-203 (1998)
• [Publications] Imoto,M.: "Inhibition of cyclin D1 expression and induction of apoptosis by inostamycin in small cell lung carcinoma cells" Jpn.J.Cancer Res.89. 315-322 (1998)
• [Publications] T.Watanabe: "Synthesis of fluorescent substrates for protein tyrosine phosphatase assays." Bioorg.Med.Chem.Lett.8. 1301-1302 (1998)
• [Publications] E.Tashiro: "Caspase-3 activation is not responsible for vinblastine-induced Bcl-2 phosphorylation and G2/M arrest in human small cell lung carcinoma Ms-1 cells." Jpn.J.Cancer Res.,-. 89. 940-946 (1998)
• [Publications] S.Simizu: "Potentiation of paclitaxel cyto toxicityy by inostamycin in human small cell lung carci noma,Ms-1 cells." Jpn.J.Cancer Res.,-. 89. 970-976 (1998)
• [Publications] S.Simizu: "Requirement of caspase-3(like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs." J.Biol.Chem.273. 26900-26907 (1998)
• [Publications] Dan,S.: "Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR-ABL tyrosine kinase,CGP 57148." Cell Death & Differ.,:. 5. 710-715 (1998)
• [Publications] Haga,N.: "2-Deoxyglucose inhibits chemotherapeutic drug-induced apoptosis in human monocytic leukemia U937 cells with inhibition of c-jun N-terminal kinase 1/stress-activated protein kinase activation." Int.J.Cancer. 76. 86-90 (1998)
• [Publications] Dong,J.: "Genetically recessive mutant of human monocytic leukemia U937 resistant to tumor necrosis factor-alpha-induced apoptosis." J.Cell.Physiol.174. 179-185 (1998)
• [Publications] Mikami,K.: "Immunological quantitation of DT-diaphorase in carcinoma cell lines and clinical colon cancers: Advanced tumors express greater levels of DT-diaphorase" Jpn.J.Cancer Res.89. 910-915 (1998)
• [Publications] Dong,J.: "Establishment of a mutant from human monocytic leukemia U937 that exhibits a genetically dominant resistance to TNFa-induced apoptosis." Apoptosis. 3. 245-254 (1998)
• [Publications] Naito,M.: "Therapeutic approach to drug resistant tumors." Ther.Drug Monit.20. 577-580 (1998)
• [Publications] Chen,Z.: "ASK1 mediates apoptotic cell death induced by genotoxic stress." Oncogene. 18. 173-180 (1998)
• [Publications] Dan,S.: "Activation of c-Abl tyrosine kinase requires caspase activation and is not involved in JNK/SAPK activation during apoptosis of human monocytic leukemia U937 cells." Oncogene. (in press). (1998)
• [Publications] Hayakawa,Y.: "Adenopeptin,A new apoptosis inducer in transformed cells from Chrysosporium sp." Tetrahedron. 54. 15871-15878 (1998)
• [Publications] Hayakawa,Y.: "Adenopeptin,a new apoptosis inducer in transformed cells from Chrysosporium sp." Tetrahedron. 54. 15871-15878 (1998)
• [Publications] Yamashita,N.: "New ravidomycin analogues,FE35A and FE35B,apoptosis inducers produced by Streptomyces rochei." J.Antibiot.51. 1105-1108 (1998)
• [Publications] Kim,J.: "Oximidines I and II: Novel antitumor macrolides from Pseudomonas sp." J.Org.Chem.64. 153-155 (1998)
• [Publications] Nishiya,N.: "Hic-5,a paxillin homologue,binds to the protein tyrosine phosphatase PEST(PTP-PEST) through its LIM3 domain." J.Biol.Chem.,in press.in press (1998)
• [Publications] Nishiya,N.: "The LIM domains of hic-5 protein recognize specific DNA fragments in a zinc-dependent manner in vitro." Nucl.Acids Res.26. 4267-4273 (1998)
• [Publications] Nose,K.: "Increase in telomere sequence-binding activity in normal human fibroblasts in senescence or in cells treated with phorbol ester or N-methyl-N'-nitro-N-nitrosoguanidine." Biol.Pharm.Bullet.21. 911-913 (1998)
• [Publications] Egawa,K.: "Identification of active substances from Streptomyces culture fluids using p-53-independent expression of p21-WAF1/Cip1 gene and their mode of action." Biol.Pharm.Bullet.21. 899-904 (1998)
• [Publications] Shibanuma,M.: "Forced expression of hic-5,a senescence-related gene,enhances differentiation phenotypes of RCT-1 cells induced by retinoid acid." Int.J.Biochem.Cell Biol.:-. 30. 39-45 (1998)
• [Publications] Rho M.-C: "Enhancement of drug accumulation by andrastin A produced by Penicillium sp.FO-3929 in vincristine-resistant KB cells." J.Antibiotics. 51. 68-72 (1998)
• [Publications] Kam T.-S.: "Conodiparines A-D,new bisindoles from Tabernaemontana.Reversal of vincristine resistance with cultured cells." Bioorganic & Medical Chemistry Letters. 8. 1693-1696 (1998)
• [Publications] Kam T.-S.: "Reversal of multidrug resistance(MDR)by aspidofractinine-type indole alkaloids." Bioorganic & Medical Chemistry Letters. 8. 2769-2772 (1998)
• [Publications] Rho M.-C.: "Revarsal of multidrug resistance by kopsiflorine isolated from Kopsi dasyrachis." Planta Medica. (in press). (1998)
• [Publications] Fukami A.: "New members of macrosphelide from Microsphaeropsis sp.FO-5050IV." J.Antibiotics. (in press).
• [Publications] Abe,M.: "Cell-associated activation of latent transforming growth factor-b by calpain." J.Cell.Physiol.174. 186-193 (1998)
• [Publications] Takahashi,H.: "Clotrimazole,an imidazole antimycotic,is a potent inhibitor of angiogenesis." Jpn.J.Cancer,Res.89. 445-451 (1998)
• [Publications] Tanaka,K.: "Induction of Ets-1 in endothelial cells during re endothelialization after denuding injury." J.Cell.Physiol.176. 235-244 (1998)
• [Publications] Oda,N.: "ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin b3." J.Cell.Physiol.178. 121-132 (1999)
• [Publications] Kanno,S.: "Establishment of a simple and practical procedure applicable to therapeutic angiogenesis." Circulation. (in press).
• [Publications] Nishimura,M.: "Angiopoietin-3,a novel member of the angiopoietin family." FEBA Lett.(in press).