請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16497
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 黃德富 | |
dc.contributor.author | Kuan-Ting Lin | en |
dc.contributor.author | 林冠廷 | zh_TW |
dc.date.accessioned | 2021-06-07T18:17:40Z | - |
dc.date.copyright | 2012-03-02 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-02-08 | |
dc.identifier.citation | References
Abedi H, Zachary I (1997) Vascular endothelial growth factor stimulates tyrosine phosphorylation and recruitment to new focal adhesions of focal adhesion kinase and paxillin in endothelial cells. J Biol Chem 272(24): 15442-15451. Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL (2001) Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61(7): 2911-2916. Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA (2003) Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301(5629): 94-96. Alitalo K, Carmeliet P (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1(3): 219-227. Alladina SJ, Song JH, Davidge ST, Hao C, Easton AS (2005) TRAIL-induced apoptosis in human vascular endothelium is regulated by phosphatidylinositol 3-kinase/Akt through the short form of cellular FLIP and Bcl-2. J Vasc Res 42(4): 337-347. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6): 401-410. Berra E, Milanini J, Richard DE, Le Gall M, Vinals F, Gothie E, Roux D, Pages G, Pouyssegur J (2000) Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol 60(8): 1171-1178. Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8(12): 967-975. Bond M, Fabunmi RP, Baker AH, Newby AC (1998) Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. FEBS Lett 435(1): 29-34. Bondavalli F, Bruno O, Ranise A, Schenone P, Losasso C, Stella L, de Paola C, Ioia N, Marmo E (1990) 3,5-Diphenyl-1H-pyrazole derivatives. VI--Esters and 2-dialkylaminoethyl ethers of 1(2-hydroxy-2-phenylethyl)-3,5-diphenyl-1H-pyrazole and N,N-disubstituted 1-(2-amino-2-phenylethyl)-3,5-diphenyl-1H-pyrazoles with depressant and platelet antiaggregating activities. Farmaco 45(5): 511-526. Brill A, Elinav H, Varon D (2004) Differential role of platelet granular mediators in angiogenesis. Cardiovasc Res 63(2): 226-235. Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O'Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60(7): 1878-1886. Bryan BA, D'Amore PA (2007) What tangled webs they weave: Rho-GTPase control of angiogenesis. Cell Mol Life Sci 64(16): 2053-2065. Bussolino F, Mantovani A, Persico G (1997) Molecular mechanisms of blood vessel formation. Trends Biochem Sci 22(7): 251-256. Caine GJ, Lip GY, Stonelake PS, Ryan P, Blann AD (2004) Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma. Thromb Haemost 92(1): 185-190. Carden CP, Larkin JM, Rosenthal MA (2008) What is the risk of intracranial bleeding during anti-VEGF therapy? Neuro Oncol 10(4): 624-630. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6): 653-660. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438(7070): 932-936. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801): 249-257. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347): 298-307. Cee VJ, Cheng AC, Romero K, Bellon S, Mohr C, Whittington DA, Bak A, Bready J, Caenepeel S, Coxon A, Deak HL, Fretland J, Gu Y, Hodous BL, Huang X, Kim JL, Lin J, Long AM, Nguyen H, Olivieri PR, Patel VF, Wang L, Zhou Y, Hughes P, Geuns-Meyer S (2009) Pyridyl-pyrimidine benzimidazole derivatives as potent, selective, and orally bioavailable inhibitors of Tie-2 kinase. Bioorg Med Chem Lett 19(2): 424-427. Chung AS, Lee J, Ferrara N (2010) Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer 10(7): 505-514. Cook KM, Figg WD (2010) Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 60(4): 222-243. Davis GE, Bayless KJ, Mavila A (2002) Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices. Anat Rec 268(3): 252-275. Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2008) A dialogue between the hypoxia-inducible factor and the tumor microenvironment. Cancer Microenviron 1(1): 53-68. Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, Moore MA, Rafii S (2000) Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest 106(4): 511-521. Dimmeler S, Zeiher AM (2000) Endothelial cell apoptosis in angiogenesis and vessel regression. Circ Res 87(6): 434-439. Dor Y, Porat R, Keshet E (2001) Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol Cell Physiol 280(6): C1367-1374. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315(26): 1650-1659. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5): 1029-1039. Fan TP, Yeh JC, Leung KW, Yue PY, Wong RN (2006) Angiogenesis: from plants to blood vessels. Trends Pharmacol Sci 27(6): 297-309. Fang J, Zhou Q, Liu LZ, Xia C, Hu X, Shi X, Jiang BH (2007) Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis 28(4): 858-864. Farag AM, Mayhoub AS, Barakat SE, Bayomi AH (2008) Regioselective synthesis and antitumor screening of some novel N-phenylpyrazole derivatives. Bioorg Med Chem 16(2): 881-889. Ferrara N (2004) Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 9 Suppl 1: 2-10. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6): 669-676. Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438(7070): 967-974. Fidler IJ, Ellis LM (1994) The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79(2): 185-188. Folberg R, Hendrix MJ, Maniotis AJ (2000) Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 156(2): 361-381. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6(4): 273-286. Folkman J (1995) Clinical Applications of Research on Angiogenesis. N Engl J Med 333(26): 1757-1763. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21): 1182-1186. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82(1): 4-6. Fraisl P, Mazzone M, Schmidt T, Carmeliet P (2009) Regulation of angiogenesis by oxygen and metabolism. Dev Cell 16(2): 167-179. Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11(2): 123-134. Genin MJ, Biles C, Keiser BJ, Poppe SM, Swaney SM, Tarpley WG, Yagi Y, Romero DL (2000) Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives. J Med Chem 43(5): 1034-1040. Gerber HP, Dixit V, Ferrara N (1998) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 273(21): 13313-13316. Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91(3): 1071-1121. Gordon MS, Cunningham D (2005) Managing patients treated with bevacizumab combination therapy. Oncology 69 Suppl 3: 25-33. Gorski DH, Mauceri HJ, Salloum RM, Halpern A, Seetharam S, Weichselbaum RR (2003) Prolonged treatment with angiostatin reduces metastatic burden during radiation therapy. Cancer Res 63(2): 308-311. Grosjean J, Kiriakidis S, Reilly K, Feldmann M, Paleolog E (2006) Vascular endothelial growth factor signalling in endothelial cell survival: a role for NFkappaB. Biochem Biophys Res Commun 340(3): 984-994. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8(2): 128-135. Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY, Hebbel RP (1999) VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res 247(2): 495-504. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3): 353-364. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5): 1011-1027. Hiraga T, Kizaka-Kondoh S, Hirota K, Hiraoka M, Yoneda T (2007) Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer. Cancer Res 67(9): 4157-4163. Holmes K, Roberts OL, Thomas AM, Cross MJ (2007) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 19(10): 2003-2012. Hori A, Imaeda Y, Kubo K, Kusaka M (2002) Novel benzimidazole derivatives selectively inhibit endothelial cell growth and suppress angiogenesis in vitro and in vivo. Cancer Lett 183(1): 53-60. Huang C, Li J, Song L, Zhang D, Tong Q, Ding M, Bowman L, Aziz R, Stoner GD (2006) Black raspberry extracts inhibit benzo(a)pyrene diol-epoxide-induced activator protein 1 activation and VEGF transcription by targeting the phosphotidylinositol 3-kinase/Akt pathway. Cancer Res 66(1): 581-587. Huang YT, Pan SL, Guh JH, Chang YL, Lee FY, Kuo SC, Teng CM (2005) YC-1 suppresses constitutive nuclear factor-kappaB activation and induces apoptosis in human prostate cancer cells. Mol Cancer Ther 4(10): 1628-1635. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23): 2335-2342. Italiano JE, Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet {alpha} granules and differentially released. Blood 111(3): 1227-1233. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21: 247-269. Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52(11): 2745-2756. Jain S, Harris J, Ware J (2010) Platelets: linking hemostasis and cancer. Arterioscler Thromb Vasc Biol 30(12): 2362-2367. Jiang BH, Liu LZ (2008) AKT signaling in regulating angiogenesis. Curr Cancer Drug Targets 8(1): 19-26. Kaelin WG, Jr., Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30(4): 393-402. Karkkainen MJ, Petrova TV (2000) Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19(49): 5598-5605. Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2(10): 727-739. Kieran MW, Turner CD, Rubin JB, Chi SN, Zimmerman MA, Chordas C, Klement G, Laforme A, Gordon A, Thomas A, Neuberg D, Browder T, Folkman J (2005) A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 27(11): 573-581. Kirk RI, Sanderson MR, Lerea KM (2000) Threonine phosphorylation of the beta 3 integrin cytoplasmic tail, at a site recognized by PDK1 and Akt/PKB in vitro, regulates Shc binding. J Biol Chem 275(40): 30901-30906. Kubota Y, Kleinman HK, Martin GR, Lawley TJ (1988) Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J Cell Biol 107(4): 1589-1598. Kuo HL, Lien JC, Chung CH, Chang CH, Lo SC, Tsai IC, Peng HC, Kuo SC, Huang TF (2010) NP-184[2-(5-methyl-2-furyl) benzimidazole], a novel orally active antithrombotic agent with dual antiplatelet and anticoagulant activities. Naunyn Schmiedebergs Arch Pharmacol 381(6): 495-505. Labelle M, Begum S, Hynes RO (2011) Direct Signaling between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis. Cancer Cell 20(5): 576-590. Leavesley DI, Schwartz MA, Rosenfeld M, Cheresh DA (1993) Integrin beta 1- and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms. J Cell Biol 121(1): 163-170. Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, Boucher Y (2000) Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60(19): 5565-5570. Leighl NB, Bennouna J, Yi J, Moore N, Hambleton J, Hurwitz H (2011) Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study. Br J Cancer 104(3): 413-418. Li SH, Shin DH, Chun YS, Lee MK, Kim MS, Park JW (2008) A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha}. Mol Cancer Ther 7(12): 3729-3738. Liu CZ, Hur BT, Huang TF (1996) Measurement of glycoprotein IIb/IIIa blockade by flow cytometry with fluorescein isothiocyanate-conjugated crotavirin, a member of disintegrins. Thromb Haemost 76(4): 585-591. Liu J, Zhan M, Hannay JA, Das P, Bolshakov SV, Kotilingam D, Yu D, Lazar AF, Pollock RE, Lev D (2006a) Wild-type p53 inhibits nuclear factor-kappaB-induced matrix metalloproteinase-9 promoter activation: implications for soft tissue sarcoma growth and metastasis. Mol Cancer Res 4(11): 803-810. Liu YN, Pan SL, Peng CY, Guh JH, Huang DM, Chang YL, Lin CH, Pai HC, Kuo SC, Lee FY, Teng CM (2006b) YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] inhibits neointima formation in balloon-injured rat carotid through suppression of expressions and activities of matrix metalloproteinases 2 and 9. J Pharmacol Exp Ther 316(1): 35-41. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MA, Hajjar KA, Manova K, Benezra R, Rafii S (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7(11): 1194-1201. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL (2005) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105(2): 659-669. Mirshahi P, Toprak SK, Faussat AM, Dubrulle S, Marie JP, Soria C, Soria J, Mirshahi M (2006) Malignant hematopoietic cells induce an increased expression of VEGFR-1 and VEGFR-3 on bone marrow endothelial cells via AKT and mTOR signalling pathways. Biochem Biophys Res Commun 349(3): 1003-1010. Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5(5): 429-441. Morales-Ruiz M, Fulton D, Sowa G, Languino LR, Fujio Y, Walsh K, Sessa WC (2000) Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. Circ Res 86(8): 892-896. Mukhopadhyay D, Nagy JA, Manseau EJ, Dvorak HF (1998) Vascular permeability factor/vascular endothelial growth factor-mediated signaling in mouse mesentery vascular endothelium. Cancer Res 58(6): 1278-1284. Mukhopadhyay T, Sasaki J, Ramesh R, Roth JA (2002) Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Cancer Res 8(9): 2963-2969. Munoz-Chapuli R, Quesada AR, Angel Medina M (2004) Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci 61(17): 2224-2243. Nicolai E, Goyard J, Benchetrit T, Teulon JM, Caussade F, Virone A, Delchambre C, Cloarec A (1993) Synthesis and structure-activity relationships of novel benzimidazole and imidazo[4,5-b]pyridine acid derivatives as thromboxane A2 receptor antagonists. J Med Chem 36(9): 1175-1187. Nicosia RF, Ottinetti A (1990) Modulation of microvascular growth and morphogenesis by reconstituted basement membrane gel in three-dimensional cultures of rat aorta: a comparative study of angiogenesis in matrigel, collagen, fibrin, and plasma clot. In Vitro Cell Dev Biol 26(2): 119-128. Okada F, Rak JW, Croix BS, Lieubeau B, Kaya M, Roncari L, Shirasawa S, Sasazuki T, Kerbel RS (1998) Impact of oncogenes in tumor angiogenesis: mutant K-ras up-regulation of vascular endothelial growth factor/vascular permeability factor is necessary, but not sufficient for tumorigenicity of human colorectal carcinoma cells. Proc Natl Acad Sci U S A 95(7): 3609-3614. Pan SL, Guh JH, Peng CY, Wang SW, Chang YL, Cheng FC, Chang JH, Kuo SC, Lee FY, Teng CM (2005) YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] inhibits endothelial cell functions induced by angiogenic factors in vitro and angiogenesis in vivo models. J Pharmacol Exp Ther 314(1): 35-42. Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269(41): 25646-25654. Passaniti A, Taylor RM, Pili R, Guo Y, Long PV, Haney JA, Pauly RR, Grant DS, Martin GR (1992) A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Invest 67(4): 519-528. Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6): 873-887. Pouessel D, Culine S (2008) High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor. Eur Urol 53(2): 376-381. Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9(6): 677-684. Raftopoulou M, Hall A (2004) Cell migration: Rho GTPases lead the way. Dev Biol 265(1): 23-32. Ranpura V, Hapani S, Wu S (2011) Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 305(5): 487-494. Rousseau S, Houle F, Landry J, Huot J (1997) p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15(18): 2169-2177. Scappaticci FA (2002) Mechanisms and future directions for angiogenesis-based cancer therapies. J Clin Oncol 20(18): 3906-3927. Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, Bergsland E, Ngai J, Holmgren E, Wang J, Hurwitz H (2007) Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99(16): 1232-1239. Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4(12): 937-947. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29(5): 625-634. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10): 721-732. Shono T, Ono M, Izumi H, Jimi SI, Matsushima K, Okamoto T, Kohno K, Kuwano M (1996) Involvement of the transcription factor NF-kappaB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. Mol Cell Biol 16(8): 4231-4239. Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S, Iruela-Arispe L, Simon MC, Keith B (2009) Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Blood 114(2): 469-477. Sowter HM, Raval RR, Moore JW, Ratcliffe PJ, Harris AL (2003) Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 63(19): 6130-6134. Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, Ferrara N, Johnson RS (2004) Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6(5): 485-495. Tanne JH (2011) FDA cancels approval for bevacizumab in advanced breast cancer. BMJ 343: d7684. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269(43): 26988-26995. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 7(10): 3129-3140. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6): 393-410. Won MS, Im N, Park S, Boovanahalli SK, Jin Y, Jin X, Chung KS, Kang M, Lee K, Park SK, Kim HM, Kwon BM, Lee JJ (2009) A novel benzimidazole analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway. Biochem Biophys Res Commun 385(1): 16-21. Wu CC, Ko FN, Kuo SC, Lee FY, Teng CM (1995) YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase. Br J Pharmacol 116(3): 1973-1978. Yeh WL, Lu DY, Lin CJ, Liou HC, Fu WM (2007) Inhibition of hypoxia-induced increase of blood-brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression. Mol Pharmacol 72(2): 440-449. Yoshiji H, Kuriyama S, Hicklin DJ, Huber J, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H (2001) The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model. Hepatology 33(4): 841-847. Yuan A, Yu CJ, Luh KT, Kuo SH, Lee YC, Yang PC (2002) Aberrant p53 expression correlates with expression of vascular endothelial growth factor mRNA and interleukin-8 mRNA and neoangiogenesis in non-small-cell lung cancer. J Clin Oncol 20(4): 900-910. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK (1996) Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci U S A 93(25): 14765-14770. Zetter BR (2008) The scientific contributions of M. Judah Folkman to cancer research. Nat Rev Cancer 8(8): 647-654. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16497 | - |
dc.description.abstract | 失調的血管新生促使了許多疾病的演進,血管生長不良會造成心肌梗塞、中風、神經性退化疾病等,而過分生長或是不正常的血管則會促進癌症、眼部退化疾病和其它發炎相關疾病,因此,調控血管新生的過程提供了一個治療這些疾病的方向。腫瘤引發之血管新生是一個多項步驟的過程,在過程中,癌細胞誘發現有血管生成新的血管貼附。血管內皮生長因子是一個強力的血管新生誘發分子,它能被癌細胞所分泌,血管內皮生長因子能誘發內皮細胞增生、移行、分化來形成新的血管網絡以供給癌細胞生長。由於有多種的細胞和各種不同的拮抗或誘發血管新生分子參與其中過程,這提供了我們許多藥物研發的標的。雖然有數種抗血管新生藥物已經批准而臨床使用於治療眼部退化疾病和癌症,但是由它們的臨床結果,副作用以及產生的抗藥性來看,目前抗血管新生的治療仍然存在一定的挑戰。因此,繼續探索及發展新的抗血管新生藥物仍有其必要性。
在本論文中,我們研究兩種系列化合物NP-184和bp5250,它們經由生物活性篩選以確定其抑制血管新生的潛力。NP-184和bp5250都能呈現濃度相關性地抑制人類臍靜脈內皮細胞的增生、移行和管狀生成,它們也濃度相關性的抑制了活體外大鼠主動脈環的管腔生成現象,在體內實驗的部分,NP-184和bp5250都能在Matrigel plug assay中依劑量相關性地抑制血管內皮生長因子所誘發的血管新生。在血管內皮生長因子所誘發的訊息傳遞途徑分析中,NP-184降低了ERK和AKT的磷酸化以及NF-kappaB移轉到細胞核。而bp5250則減少了ERK, p38, PI3K, AKT, FAK, Src, Rac1/Cdc42和Rho的活化,另外在缺氧情況下,bp5250抑制了HIF-1alfa和血管內皮生長因子mRNA的表現。考量這兩個化合物亦具有明顯的抗血小板活性,NP-184和bp5250具有發展成双重功能的抗腫瘤血管新生的潛力。在未來的工作展望上,除了對於作用機制的進一步探討外,還希望藉由它們與標的結構的循理設計和活性分析的協助,來發展更具有抑制血管新生活性的藥物。 | zh_TW |
dc.description.abstract | Dysregulated angiogenesis contributes to various diseases progression. Insufficient blood vessels growth causes myocardial infarction, stroke, and neuro-degeneration disorders while overgrowth or abnormal blood vessels promote malignant tumor, retinopathy and inflammatory diseases. Therefore, modulating angiogenesis processes provide a therapeutic direction for disease treatment. Tumor angiogenesis is a multistep process by which tumor cell induces new capillaries from pre-existing vessels. Vascular endothelial growth factor (VEGF) is a potent angiogenesis inducer which can be released by tumor cells. VEGF induces endothelial cell proliferation, migration and differentiation to form new vasculature for supporting tumor growth. Owing to the multi-involvement on types of cells and varieties of pro- and anti-angiogenic molecules, it reveals many target sites for the drug development. Although several anti-angiogenic drugs have been approved for eye degeneration and cancer treatments, the clinical outcomes, side effects and resistance remain challenges in these therapies.
In this report, we presented two serial derivative compounds, NP-184 and bp5250, which were screened for the inhibitory effect on angiogenesis by bioactivity assays. Both NP-184 and bp5250 inhibit the VEGF-induced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) in a concentration- dependent manner. They also suppress the capillary sprouting from rat aortic ring ex vivo. As in vivo assay, NP-184 and bp5250 both dose-dependently repress new vessels invasion to the plugs in the VEGF induced Matrigel assay. In the VEGF activated signaling level, NP-184 reduces the phosphorylation of ERK and AKT, and NF-kappaB translocation while bp5250 decreases the activation of ERK, p38, PI3K, AKT, FAK, Src, Rac1/cdc42 and Rho. In addition, bp5250 inhibits the expression of HIF-1alfa and VEGF mRNA expression. Along with their additional antiplatelet activity, both compounds may provide additional advantages in vivo for suppression of tumor-induced angiogenesis, and hypercoagulation-induced tumor metastasis. However, detailed molecular mechanisms still need to be further investigated. Besides, optimization of the lead compounds by rational design and functional assays for improvement of potency is also required. | en |
dc.description.provenance | Made available in DSpace on 2021-06-07T18:17:40Z (GMT). No. of bitstreams: 1 ntu-101-D90443003-1.pdf: 5340459 bytes, checksum: b703316e853c1678bf245da874ba1699 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | Contents
口試委員會審定書 ……………………………………………………… i 誌謝 ………………………………………………………………………ii 中文摘要 …………………………………………………………………iii Abstract ……………………………………………………………………v Abbreviations …………………………………………………………… vii Chapter 1 Introduction ………………………………………………………………1 Chapter 2 A novel compound, NP-184, inhibits the vascular endothelial growth factor induced angiogenesis ……………………………………………30 Chapter 3 Bp5250 inhibits vascular endothelial growth factor-induced angiogenesis and HIF-1α expression on endothelial cells …………… 59 Chapter 4 Conclusion and Perspectives……………………………………………87 References ………………………………………………………………94 Publication List …………………………………………………………107 | |
dc.language.iso | en | |
dc.title | 合成物NP-184和bp5250對血管新生拮抗作用與機制之探討 | zh_TW |
dc.title | The inhibitory effects and mechanisms of novel compounds, NP-184 and bp5250 on angiogenesis | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 鄧哲明,顏茂雄,楊春茂,吳文彬 | |
dc.subject.keyword | 血管新生,血管內皮生長因子,內皮細胞, | zh_TW |
dc.subject.keyword | Angiogenesis,VEGF,Endothelial cell, | en |
dc.relation.page | 107 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2012-02-08 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-101-1.pdf 目前未授權公開取用 | 5.22 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。