がん増悪因子とその制御に作用する制がん物質の研究

1994 Fiscal Year Annual Research Report

• Project/Area Number: 06282122
• 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 富山医薬大, 和漢薬研, 教授 (80133776) ; 小宮山 寛機 北里研究所, 基礎研, 副所長 (00106676) ; 小河原 宏 明治薬科大学, 教授 (00097198) ; 岡田 信子 国立がんセンター研究所, 主任研究官 (70194363) ; 岡部 實裕 北大医, 付属病院, 助手 (40113534)
• Keywords: がん遺伝子 / シグナル伝達 / 制がん剤 / がん抑制遺伝子 / IL-6 / 転移 / 血管新生 / 薬剤耐性

Research Abstract

1.がん化シグナル抑制物質の探索のために、足場非依存細胞増殖の簡便迅速な測定法を開発した。
2.チロシンキナーゼやRasおよびPI3Kなどのシグナル伝達系に作用する物質の探索と制がん作用の解析を行い、ハービマイシンの抗腫瘍効果、IT-62-BのRas阻害作用、K252aのPI3K阻害作用、azatyrosineにより誘導されるCa-31遺伝子のがん化抑制作用などを明らかにした。
3.がん抑制遺伝子を活性化する物質の探索系から、anguinomycin類を見いだした。
4.IL-6シグナル伝達経路を解析し、H7に感受性の未知のキナーゼがSTATの転写活性化に関与すること、また、IL-6の産生調節物質の探索系から、2種類の新規化合物を見いだし、化学構造を決定した。
5.転移を抑制するbestatinの作用の研究から、膜結合型アミノペプチダーゼが転移制御の標的になること、およびradicicolの誘導体が血管新生を阻害し抗腫瘍効果を発揮することを示した。
6.ヒト胃がん5FU耐性株の耐性機構を解析し、deoxy-inosineが5FUの感受性を回復させること、また、多剤耐性がん細胞へのM-CSFなどのサイトカイン遺伝子の導入により、抗P糖蛋白抗体の治療効果が増強することを見いだした。

Research Products

• [Publications] Fukuzawa,H: "Labeling of v-Src and BCR-ABL tyrosine kinases with [^<14>C]herbimycin A and its use in the elucidation of kinase inactivation mechanism." FEBS Letters. 340. 155-158 (1994)
• [Publications] Murakami,Y: "Conversion of epidermal growth factor (EGF) into a stimulatory ligand for A431-cell growth by herbimycin A by decreasing the level of expression of EGF receptor." Biochemical Journal. 301. 57-62 (1994)
• [Publications] Murakami,Y.: "Accelerated degradation of 160 kDa EGF receptor precursor by the tyrosine kinase inhibitor herbimycin A in the endoplasmic reticulum of A431 human epidermoid carcinoma cells.Biochem." Biochemical Journal. 301. 63-68 (1994)
• [Publications] Beaty,C.D.: "Lipopolysaccharide induced cytokine production in human monocytes:role of tyrosine phosphorylation in transmembrane signal transduction." European Journal of Immunology. 24. 1278-1284 (1994)
• [Publications] Kanbe,T.: "Use of transcriptional enhancer elements responsive to Ras,protein kinase A and protein kinase C to evaluate inhibitors of specific signal transduction pathways." Biological Pharmacentical Bulleti22GD05:17. 779-783 (1994)
• [Publications] Okabe,M.: "Effect of herbimycin A,and inhibitor of tyrosine kinase,on protein tyrosine kinase activity and phosphotyrosyl proteins of Ph^1-positive leukemia cells." Leukemia Research. 18. 213-220 (1994)
• [Publications] Okabe,M: "In vivo antiumor acitvity of herbimycin A,a tyrosine kinase inhibitor,targeted against BCR/ABL oncoprotein in mice bearing BCR/ABL transfected cells." Leukemia Research. 18. 867-873 (1994)
• [Publications] Higa,T.: "Establishment and characterization of a new Ph^1-positive ALL cell line (ALL/MIK)presenting bcr gene rearrangement on bcr-2 and LL-type transcript:Suggestion of in vitro differentiation to monocytoid lineage." Leukemic & Lyrphoma. 12. 287-296 (1994)
• [Publications] Kurosawa,M.: "p53 Gene mutation in the chronic phase was not detected in the myeloid crisis of a chronic myelocytic leukemia case." Blood. 83. 2750-2752 (1994)
• [Publications] Kunieda,Y.: "Chronic myeloid leukemia presenting ALL-type BCR/ABL transcript." Ann.Hematol.69. 189-193 (1994)
• [Publications] Okabe,M.: "Establishment and characterization of a new Ph1-positive chronic myeloid leukemia cell line MC3 with tri-lineage phenotype and an altered p53 gene." Leuk.Lymph.(in press).
• [Publications] Kunieda,Y.: "Effect of rhG-CSF on infection complications and impaired function of neutrophils secondary to chemotherapy for non-Hodgkin's lymphoma." Leuk.Lymph.(in press).
• [Publications] Kanbe,T.: "Phenotypic reversion induced by anthracyclines in ras oncogene-expressed calls;structure-activity relationships." Biol.Pharm.Bull.17. 527-530 (1994)
• [Publications] Tsuchiya,KS.: "Monoclonal antibody raised against apopretein of C-1027;effect on biochemical and biological activities of the holoantibiotic." J.Antibiotics. 47. 787-791 (1994)
• [Publications] Higashi,K.: "Daidzein inhibits insulin-or insulin-like growth factor-1-mediated signaling in cell cycle progression of Swiss 3T3 cell." Biochim.Biophys.Acta22GD15:1221. 29-35 (1994)
• [Publications] Ogawara,H.: "Inhibitors of diacylglycerol kinase from Drechslera sacchari." J.Antibiotics. 47. 499-501 (1994)
• [Publications] Ishigami,K.: "Cororubicin,a new anthracycline antibiotic generating active oxygen in tumor cells." J.Antibiotics. 47. 1219-1225 (1994)
• [Publications] Kamishohara,M.: "Antitumor activity of SPM VIII,a derivative of the nucleoside antibiotic spicamycin,against human tumor xenografts." J.Antibiotics. 47. 1305-1311 (1994)
• [Publications] Hayakawa,Y.: "Menoxymycins A and B,antitumor antibiotics generating active oxygen in tumor cells." J.Antibiotics. 47. 1344-1347 (1994)
• [Publications] Fujitani,Y.: "Transcriptional activation of the IL-6 response element in the junB promoter is mediated by multiple Stat family proteins." Biochem.Biophys.Res.Comnun.202. 1181-1187 (1994)
• [Publications] Takeda,T.: "E1A repression of IL-6-induced gene activation by blocking the assembly of IL-6 response element binding complexes." J.Immunol. 153. 4573-4582 (1994)
• [Publications] Nakajima,K.: "Interleukin 6 receptor-mediated signal transduction pathways." Gann Monograph on Cancer Res.42. 37-49 (1994)
• [Publications] Nakajima,K.: "Signal transduction through IL-6 receptor:Involvement of multiple protein kinase,Stat factors and a novel H7-sensitive pathway." Ann.Nwe York Acad.Sci.(in press).
• [Publications] Otani,N.: "Influence of growth factors on in vitro invasiveness and type IV collagenolysis of human renal cell carcinoma cells." J.Urol.151. 223-226 (1994)
• [Publications] Kobayashi,T.: "Cell-surface sulfoglycolipids are involved in the attachment of renal-cancer cells to laminin." Int.J.Cancer. 56. 281-285 (1994)
• [Publications] Yoo,Y,C.: "MDP-Lys(L18),a lipophilic derivative of muramyl dipeptide,inhibits the metastasis of haematogenous and nonhaematogenous tumours in mice." Vaccine. 12. 175-180 (1994)
• [Publications] Saiki,I.: "Influence of fibroblasts on the invasion and migration of highly or weakly metastatic B16 melanoma cells." Int,J.Cancer. 56. 867-873 (1994)
• [Publications] Saiki,I.: "Antiadhesion peptides in the prevention of tumour metastasis." Clin.Immuuother.1. 307-318 (1994)
• [Publications] Masumori,N.: "Inhibitory effect of minocycline on in vitro invasion and experimental metastasis of mouse renal adenocarcinoma." J.Urol. 151. 1400-1404 (1994)
• [Publications] Sato,K.: "Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng,ginsenoside-Rb2." Biol.Pharm.Bull.17. 635-639 (1994)
• [Publications] Yoneda,J.: "Inhibitory effect of recombinant fibronectin polypeptides inhibit adhesion of liver-metastatic lymphoma cells to hepatic sinusoidal endothelial cells followed by the tumor invasion." Jpn.J.Cancer Res.85. 723-734 (1994)
• [Publications] Yoneda,J.: "Role of the heparin-binding domain of chimeric peptides derived from fibronectin on the cell spreading and motility." Exp.Cell.Res.(in press)
• [Publications] Oikawa,T.: "Possible functional groups responsible for inhibition of in vivo angiogenesis by herbimycin A." Biol.Pharm.Bull. 17. 1430-1432 (1994)
• [Publications] Oikawa,T.: "Strategies to find novel angiogenesis inhibitors as potential therapeutic agents for cancer." Curr.Med.Chem.2. 406-417 (1994)
• [Publications] Oikawa,T.: "Three isoforms of platelet-derived growth factors all have the capability to induce angiogenesis in vivo." Biol.Pharm.Bull.(in press).
• [Publications] Inaba,M.: "Flow cytometric analysis of cell-killing actions of 5-fluorouracil in human colorectal cancer cells." Oncol.Res.6. 303-309 (1994)
• [Publications] Inaba,M.: "Different modes of cell-killing action between DNA topoisomerase I and II inhibitors revealed by kinetic analysis." Jpn.J.Caucer.Res. 85. 187-193 (1994)
• [Publications] Mizuno,K.: "Autonomous expressions of cytokine genes by human lung cancer cells and their paracrine regulation." Jpn.J.Cancer.Res.85. 179-186 (1994)
• [Publications] Yano,S.: "Cyclosporine A enhances susceptibility of multi-drug resistant human cancer cells to anti-P-glycoprotein antibody-dependent cytotoxicity of monocytes,but not of lymphocytes." Jpn.J.Cancer.Res.85. 194-203 (1994)
• [Publications] Sone,S.: "Production of IL-1 and its receptor antagonist is regulated differently by IFN-γ and IL-4 in human monocytes and alveolar macrophages." Enr.Respir.J.7. 657-663 (1994)
• [Publications] Sone,S.: "Local interleukin-2 therapy for cancer,and its effector induction mechanisms." Oncology. 51. 170-176 (1994)
• [Publications] Yano,S.: "Differential effects of anti-inflammatory cytokines(IL-4,IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor(MCAF)." J.Leukocyte Biol.(in press).
• [Publications] Numazawa,S.: "Involvement of Na^+,K^+-ATPase inhibition in K562 cell differentiation induced by bufalin." J.Cell.Physiol.160. 113-120 (1994)
• [Publications] Takii,T.: "Interleukin-1 down-regulates type I interleukin 1 receptor mRNA expression in a human fibroblast cell line TIG-1 in the absence of prostaglandin E_2 synthesis." Lymph.Cytok.Res.13. 213-219 (1994)
• [Publications] Minami,Y.: "Structure of cypemycin,a new peptide antibiotic." Tetrahed.Lett.35. 8001-8004 (1994)