進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-3107201312254000
論文名稱(中文) 利用纖維黏蛋白的第三型區域的第十個模組發展同時對VEGFR2及整合蛋白αvβ3具有雙重專一性的拮抗劑
論文名稱(英文) Development of dual VEGFR2 and integrin αvβ3-specific antagonist using the tenth module of fibronectin type III domain
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 101
學期 2
出版年 102
研究生(中文) 陳金貝
研究生(英文) Chin-Pei Chen
學號 S16004068
學位類別 碩士
語文別 中文
論文頁數 108頁
口試委員 指導教授-莊偉哲
口試委員-符文美
口試委員-陳金榜
口試委員-蕭傳鐙
中文關鍵字 纖維黏蛋白  血管內皮細胞生長因子受體  整合蛋白  血管新生 
英文關鍵字 fibronectin  VEGFR2  integrin  angiogenesis 
學科別分類
中文摘要 血管新生是指在已存在的血管上新生成新的血管,以提供腫瘤轉移所需要的養分,血管內皮細胞生長因子受體2(VEGFR2)與整合蛋白αvβ3在調控血管新生上具有重要的交互作用。在血管生成中,血管內皮細胞上VEGFR2和整合蛋白αvβ3之間的交互作用在整個過程是重要的,且VEGFR2和整合蛋白αvβ3其中一個受體活化,都能促使另外一個受體被活化,因此兩者的功能之間具有互相回饋調控的現象,這樣的互惠關係調控血管新生中很多個過程,包括血管內皮細胞遷移、存活、生長和管狀形成,因此,拮抗兩個受體的拮抗劑具有藥物發展的潛力。這裡,我們利用纖維黏蛋白第三型區域的第十個模組(10Fn3)當蛋白鷹架,發展同時拮抗VEGFR2和整合蛋白αvβ3的雙重專一性重組蛋白,整合蛋白αvβ3的10Fn3重組蛋白在我們之前的研究已表現,VEGFR2的10Fn3重組蛋白則是根據之前利用mRNA 展示技術的研究結果,而雙重專一性重組蛋白則是利用(G4S1)2或(G4S1)3連接VEGFR2和整合蛋白αvβ3的10Fn3重組蛋白。有兩個VEGFR2重組蛋白和四個雙重專一性重組蛋白已成功用大腸桿菌表現並且純化,在細胞黏著實驗顯示,雙重專一性重組蛋白保有對整合蛋白αvβ3的親和力,其IC50值約為80 nM。在血管新生實驗中,雙重專一性重組蛋白不只抑制HUVEC的生長之IC50值約為70 nM,且抑制管狀形成,其IC50值約為350 nM,特別的是,雙重專一性重組蛋白在抑制VEGF調控的HUVEC遷移具有協同性的效果,其IC50值約為130 nM,相比之下,整合蛋白αvβ3的10Fn3重組蛋白的IC50值約為2449 nM,少了至少10倍的抑制效果,而VEGFR2的10Fn3重組蛋白則只會抑制VEGF的效果。雙重專一性重組蛋白的溶解度約為0.3 mg/ml,比整合蛋白αvβ3的10Fn3重組蛋白的溶解度少93倍,雙重專一性重組蛋白的熱穩定度約為55℃,比整合蛋白αvβ3的10Fn3重組蛋白少30℃,這樣的結果顯示雙重專一性重組蛋白的溶解度與熱穩定度是需要改良的。這些研究是藉由分子工程方法提供一個新的或改進的針對VEGFR2和整合蛋白αvβ3的臨床藥物。
英文摘要 Angiogenesis is the process that new blood vessels form from pre-existing vessels and provides the nutrients for tumor metastasis. Significant cross-talk exists between vascular endothelial growth factor receptor-2 (VEGFR2) and integrin αvβ3 that mediate angiogenesis. The interaction between integrin αvβ3 and VEGFR2 on endothelial cell is an important process during vascularization. The functional association between VEGFR2 and integrin αvβ3 is of reciprocal nature because each receptor is able to promote activation of its counterpart. This mutually beneficial relationship regulates a number of cellular activities involved in angiogenesis, including endothelial cell migration, survival, proliferation and tube formation. Therefore, the agents that inhibit both receptors would have important therapeutic potential. Here, we used the tenth module of fibronectin type III domain (10Fn3) as a molecular scaffold to develop dual-specific proteins that bound to VEGFR2 and integrin αvβ3. Integrin αvβ3-specific 10Fn3 mutant was expressed according to our previous study. VEGFR2-specific 10Fn3 mutants were expressed according to the results of mRNA display study. These dual specific mutants were created by linking VEGFR2-specific and αvβ3-specific 10Fn3 mutants using the (G4S1)2 or (G4S1)3 linkers. Two VEGFR-specific and four dual-specific proteins were successfully expressed in E. coli and purified to homogeneity. Cell adhesion inhibition assay showed that dual-specific proteins can retain their inhibitory affinities to integrin αvβ3 with the IC50 value of ~80 nM. In angiogenesis assay, dual-specific proteins inhibited not only HUVEC proliferation with an IC50 value of ~70 nM but also tube formation with an IC50 value of ~350 nM. In particular, dual-specific proteins exhibited synergistic effect on the inhibition of VEGF-mediated HUVEC migration with the IC50 value of ~130 nM. In contrast, integrin αvβ3-specific 10Fn3 mutant exhibited 10-fold less inhibitory activity with an IC50 value of ~2449 nM, and VEGFR2-specific 10Fn3 mutant only inhibits VEGF effect. The solubility of dual-specific proteins is ~ 0.3 mg/ml that is ~93-fold less than that of αvβ3-specific 10Fn3 mutant. The themosatbility of dual-specific proteins is ~55℃ that is 30℃ less than that of αvβ3-specific 10Fn3 mutant. These results suggest that the solubility and thermostability of dual-specific proteins should be improved. This study on molecular engineering approach is providing new and improved sources of clinically relevant dual VEGFR2- and αvβ3-specific drugs.
論文目次 摘要 I
Abstract II
致謝 III
目錄 IV
表目錄 VII
圖目錄 VIII
附錄目錄 IX
縮寫檢索表 X
儀器 XI
第1章 緒論 1
1-1 背景資料 1
1-2 血管新生與癌症的關係 1
1-3 血管內皮生長因子 (VEGF) 與其受體的介紹 2
1-3-1 VEGF-A (VEGF) 的介紹 3
1-3-2 血管內皮生長因子受體2 (VEGFR2) 的介紹 3
1-3-3 目前與VEGF和VEGFR2相關的藥物發展 4
1-4 整合蛋白 (Integrin) 的介紹 5
1-4-1 整合蛋白αvβ3的介紹 6
1-4-2 整合蛋白αvβ3與VEGFR2之間的相互作用 7
1-4-3 發展同時拮抗VEGFR2和整合蛋白αvβ3的藥物 8
1-5 纖維黏蛋白 (Fibronectin) 的介紹 9
1-5-1 纖維黏蛋白的第三型區域的第十個模組 10
第2章 研究目標與策略 12
第3章 材料與方法 13
3-1 10Fn3重組蛋白的製備 13
3-1-1 實驗菌株、質體和培養基配方 13
3-1-2 重組基因之建構 14
3-1-3 重組蛋白的表現與純化 17
3-1-4 重組蛋白之質譜鑑定 21
3-2 細胞株及培養方法 22
3-3 雙重專一性10Fn3重組蛋白抑制細胞黏著之研究 25
3-4 檢測HUVEC表面整合蛋白與VEGFR2的表現量 27
3-5 10Fn3重組蛋白抑制HUVEC遷移能力之研究 28
3-6 10Fn3重組蛋白抑制HUVEC存活之研究 30
3-7 10Fn3重組蛋白抑制管狀形成 (tube formation) 之研究 31
3-8 10Fn3重組蛋白之蛋白質溶解度的測定 33
3-9 10Fn3重組蛋白之蛋白熱穩定的測定 34
第4章 結果 36
4-1 10Fn3重組蛋白之製備與鑑定 36
4-2 雙重專一性10Fn3重組蛋白對細胞黏著的結果 36
4-3 HUVEC表面整合蛋白與VEGFR2的表現量 37
4-4 10Fn3重組蛋白抑制HUVEC遷移能力之研究 38
4-5 10Fn3重組蛋白抑制HUVEC存活能力之研究 40
4-5-1 在血清環境下抑制HUVEC存活能力的結果 40
4-5-2 在VEGF環境下抑制HUVEC存活能力的結果 40
4-6 10Fn3重組蛋白抑制HUVEC管狀形成的結果 41
4-7 10Fn3重組蛋白的蛋白溶解度的結果 42
4-8 10Fn3重組蛋白熱穩定的結果 43
第5章 討論 44
5-1 單一專一性與雙重專一性10Fn3重組蛋白對血管新生的影響 44
5-1-1 10Fn3重組蛋白對HUVEC遷移的影響 45
5-1-2 10Fn3重組蛋白對HUVEC存活的影響 46
5-1-3 10Fn3重組蛋白對HUVEC管狀形成的影響 46
5-1-4 雙重專一性10Fn3重組蛋白具有協同性效用 47
5-2 單一專一性與雙重專一性10Fn3重組蛋白的穩定度 48
5-2-1 10Fn3重組蛋白對溶解度的影響 48
5-2-2 10Fn3重組蛋白對熱穩定的影響 48
5-3 在藥物發展上雙重專一性10Fn3重組蛋白的優勢 49
5-4 未來展望 50
第6章 結論 52
參考文獻 54
表 63
圖 70
附錄 93
自述 108
參考文獻 Ackermann, M., Carvajal, I.M., Morse, B.A., Moreta, M., O'Neil, S., Kossodo, S., Peterson, J.D., Delventhal, V., Marsh, H.N., Furfine, E.S., et al. (2011). Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in Colo205 tumor xenografts. International journal of oncology 38, 71-80.

Baeriswyl, V., and Christofori, G. (2009). The angiogenic switch in carcinogenesis. Seminars in cancer biology 19, 329-337.

Bloom, L., and Calabro, V. (2009). FN3: a new protein scaffold reaches the clinic. Drug discovery today 14, 949-955.

Borges, E., Jan, Y., and Ruoslahti, E. (2000). Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. The Journal of biological chemistry 275, 39867-39873.

Brooks, P.C. (1996). Role of integrins in angiogenesis. European journal of cancer (Oxford, England : 1990) 32A, 2423-2429.

Brooks, P.C., Clark, R.A., and Cheresh, D.A. (1994a). Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science (New York, NY) 264, 569-571.

Brooks, P.C., Montgomery, A.M., Rosenfeld, M., Reisfeld, R.A., Hu, T., Klier, G., and Cheresh, D.A. (1994b). Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157-1164.

Byzova, T.V., Goldman, C.K., Pampori, N., Thomas, K.A., Bett, A., Shattil, S.J., and Plow, E.F. (2000). A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Molecular cell 6, 851-860.

Connolly, D.T., Heuvelman, D.M., Nelson, R., Olander, J.V., Eppley, B.L., Delfino, J.J., Siegel, N.R., Leimgruber, R.M., and Feder, J. (1989). Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. The Journal of clinical investigation 84, 1470-1478.

Contois, L., Akalu, A., and Brooks, P.C. (2009). Integrins as "functional hubs" in the regulation of pathological angiogenesis. Seminars in cancer biology 19, 318-328.

Cox, D., Brennan, M., and Moran, N. (2010). Integrins as therapeutic targets: lessons and opportunities. Nature reviews Drug discovery 9, 804-820.

Desgrosellier, J.S., and Cheresh, D.A. (2010). Integrins in cancer: biological implications and therapeutic opportunities. Nature reviews Cancer 10, 9-22.

Ebos, J.M., Lee, C.R., and Kerbel, R.S. (2009). Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 15, 5020-5025.

Eliceiri, B.P., and Cheresh, D.A. (1999). The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. The Journal of clinical investigation 103, 1227-1230.

Ellis, L.M., and Hicklin, D.J. (2008). Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 6371-6375.

Emanuel, S.L., Engle, L.J., Chao, G., Zhu, R.R., Cao, C., Lin, Z., Yamniuk, A.P., Hosbach, J., Brown, J., Fitzpatrick, E., et al. (2011). A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor. mAbs 3, 38-48.

Ferrara, N., and Henzel, W.J. (1989). Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochemical and biophysical research communications 161, 851-858.

Ferrara, N., Hillan, K.J., Gerber, H.P., and Novotny, W. (2004). Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature reviews Drug discovery 3, 391-400.

Fitzgerald, J.B., Schoeberl, B., Nielsen, U.B., and Sorger, P.K. (2006). Systems biology and combination therapy in the quest for clinical efficacy. Nature chemical biology 2, 458-466.

Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. The New England journal of medicine 285, 1182-1186.

Folkman, J. (1995). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature medicine 1, 27-31.

Folkman, J. (2007). Angiogenesis: an organizing principle for drug discovery? Nature reviews Drug discovery 6, 273-286.

Folkman, J., and Haudenschild, C. (1980). Angiogenesis in vitro. Nature 288, 551-556.

Francavilla, C., Maddaluno, L., and Cavallaro, U. (2009). The functional role of cell adhesion molecules in tumor angiogenesis. Seminars in cancer biology 19, 298-309.

Garon, E.B., Cao, D., Alexandris, E., John, W.J., Yurasov, S., and Perol, M. (2012). A randomized, double-blind, phase III study of Docetaxel and Ramucirumab versus Docetaxel and placebo in the treatment of stage IV non-small-cell lung cancer after disease progression after 1 previous platinum-based therapy (REVEL): treatment rationale and study design. Clinical lung cancer 13, 505-509.

Glade-Bender, J., Kandel, J.J., and Yamashiro, D.J. (2003). VEGF blocking therapy in the treatment of cancer. Expert opinion on biological therapy 3, 263-276.

Goldoni, M., and Johansson, C. (2007). A mathematical approach to study combined effects of toxicants in vitro: evaluation of the Bliss independence criterion and the Loewe additivity model. Toxicology in vitro : an international journal published in association with BIBRA 21, 759-769.

Goodman, S.L., and Picard, M. (2012). Integrins as therapeutic targets. Trends in pharmacological sciences 33, 405-412.

Hanahan, D., and Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353-364.

Heckman, K.L., and Pease, L.R. (2007). Gene splicing and mutagenesis by PCR-driven overlap extension. Nature protocols 2, 924-932.

Hoeben, A., Landuyt, B., Highley, M.S., Wildiers, H., Van Oosterom, A.T., and De Bruijn, E.A. (2004). Vascular endothelial growth factor and angiogenesis. Pharmacological reviews 56, 549-580.

Humphries, M.J. (2001). Cell-substrate adhesion assays. Current protocols in cell biology / editorial board, Juan S Bonifacino [et al] Chapter 9, Unit 9 1.

Hynes, R.O. (1987). Integrins: a family of cell surface receptors. Cell 48, 549-554.
Hynes, R.O. (2002). Integrins: bidirectional, allosteric signaling machines. Cell 110, 673-687.

Ingber, D.E., and Folkman, J. (1989). Mechanochemical switching between growth and differentiation during fibroblast growth factor-stimulated angiogenesis in vitro: role of extracellular matrix. The Journal of cell biology 109, 317-330.

Kerbel, R.S. (2008). Tumor angiogenesis. The New England journal of medicine 358, 2039-2049.

Ketola, K., Kallioniemi, O., and Iljin, K. (2012). Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells. PloS one 7, e51470.

Kim, T.J., Landen, C.N., Lin, Y.G., Mangala, L.S., Lu, C., Nick, A.M., Stone, R.L., Merritt, W.M., Armaiz-Pena, G., Jennings, N.B., et al. (2009). Combined anti-angiogenic therapy against VEGF and integrin alphaVbeta3 in an orthotopic model of ovarian cancer. Cancer biology & therapy 8, 2263-2272.

Koide, A., Bailey, C.W., Huang, X., and Koide, S. (1998). The fibronectin type III domain as a scaffold for novel binding proteins. Journal of molecular biology 284, 1141-1151.

Le Tourneau, C., Raymond, E., and Faivre, S. (2007). Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST). Therapeutics and clinical risk management 3, 341-348.

Li, J., Huang, S., Armstrong, E.A., Fowler, J.F., and Harari, P.M. (2005). Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor-2 (VEGFR2) blockade. International journal of radiation oncology, biology, physics 62, 1477-1485.

Lipovsek, D. (2011). Adnectins: engineered target-binding protein therapeutics. Protein engineering, design & selection : PEDS 24, 3-9.

Maayah, Z.H., El Gendy, M.A., El-Kadi, A.O., and Korashy, H.M. (2013). Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation. Archives of toxicology 87, 847-856.

Mac Gabhann, F., and Popel, A.S. (2007). Dimerization of VEGF receptors and implications for signal transduction: a computational study. Biophysical chemistry 128, 125-139.

Mahabeleshwar, G.H., Chen, J., Feng, W., Somanath, P.R., Razorenova, O.V., and Byzova, T.V. (2008). Integrin affinity modulation in angiogenesis. Cell cycle (Georgetown, Tex) 7, 335-347.

Mahabeleshwar, G.H., Feng, W., Phillips, D.R., and Byzova, T.V. (2006). Integrin signaling is critical for pathological angiogenesis. The Journal of experimental medicine 203, 2495-2507.

Majumder, S., Piguet, A.C., Dufour, J.F., and Chatterjee, S. (2013). Study of the cellular mechanism of Sunitinib mediated inactivation of activated hepatic stellate cells and its implications in angiogenesis. European journal of pharmacology 705, 86-95.

Mamluk, R., Carvajal, I.M., Morse, B.A., Wong, H., Abramowitz, J., Aslanian, S., Lim, A.C., Gokemeijer, J., Storek, M.J., Lee, J., et al. (2010). Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2. mAbs 2, 199-208.

Mao, Y., and Schwarzbauer, J.E. (2005). Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix biology : journal of the International Society for Matrix Biology 24, 389-399.

Mitchell, E.P. (2013). Targeted therapy for metastatic colorectal cancer: role of aflibercept. Clinical colorectal cancer 12, 73-85.

Mulgrew, K., Kinneer, K., Yao, X.T., Ward, B.K., Damschroder, M.M., Walsh, B., Mao, S.Y., Gao, C., Kiener, P.A., Coats, S., et al. (2006). Direct targeting of alphavbeta3 integrin on tumor cells with a monoclonal antibody, Abegrin. Molecular cancer therapeutics 5, 3122-3129.

Niu, G., and Chen, X. (2011). Why integrin as a primary target for imaging and therapy. Theranostics 1, 30-47.

Palmer, D.H., Hussain, S.A., Smith, A.J., Hargreaves, S., Ma, Y.T., Hull, D., Johnson, P.J., and Ross, P.J. (2013). Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom. British journal of cancer.

Papo, N., Silverman, A.P., Lahti, J.L., and Cochran, J.R. (2011). Antagonistic VEGF variants engineered to simultaneously bind to and inhibit VEGFR2 and alphavbeta3 integrin. Proceedings of the National Academy of Sciences of the United States of America 108, 14067-14072.

Ramakrishnan, V., Bhaskar, V., Law, D.A., Wong, M.H., DuBridge, R.B., Breinberg, D., O'Hara, C., Powers, D.B., Liu, G., Grove, J., et al. (2006). Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent. Journal of experimental therapeutics & oncology 5, 273-286.

Roskoski, R., Jr. (2007). Vascular endothelial growth factor (VEGF) signaling in tumor progression. Critical reviews in oncology/hematology 62, 179-213.

Savic, R., He, X., Fiel, I., and Schuchman, E.H. (2013). Recombinant human acid sphingomyelinase as an adjuvant to sorafenib treatment of experimental liver cancer. PloS one 8, e65620.

Schagger, H., Aquila, H., and Von Jagow, G. (1988). Coomassie blue-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for direct visualization of polypeptides during electrophoresis. Analytical biochemistry 173, 201-205.

Schwartz, M.A., and Ginsberg, M.H. (2002). Networks and crosstalk: integrin signalling spreads. Nature cell biology 4, E65-68.

Senger, D.R., Galli, S.J., Dvorak, A.M., Perruzzi, C.A., Harvey, V.S., and Dvorak, H.F. (1983). Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science (New York, NY) 219, 983-985.

Singh, P., Carraher, C., and Schwarzbauer, J.E. (2010). Assembly of fibronectin extracellular matrix. Annual review of cell and developmental biology 26, 397-419.

Smith, V., Wirth, G.J., Fiebig, H.H., and Burger, A.M. (2008). Tissue microarrays of human tumor xenografts: characterization of proteins involved in migration and angiogenesis for applications in the development of targeted anticancer agents. Cancer genomics & proteomics 5, 263-273.

Soldi, R., Mitola, S., Strasly, M., Defilippi, P., Tarone, G., and Bussolino, F. (1999). Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. The EMBO journal 18, 882-892.

Somanath, P.R., Malinin, N.L., and Byzova, T.V. (2009). Cooperation between integrin avb3 and VEGFR2 in angiogenesis. Angiogenesis 12, 177-185.

Takahashi, T., Yamaguchi, S., Chida, K., and Shibuya, M. (2001). A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. The EMBO journal 20, 2768-2778.

Tamkun, J.W., DeSimone, D.W., Fonda, D., Patel, R.S., Buck, C., Horwitz, A.F., and Hynes, R.O. (1986). Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin. Cell 46, 271-282.

Tamkun, J.W., and Hynes, R.O. (1983). Plasma fibronectin is synthesized and secreted by hepatocytes. The Journal of biological chemistry 258, 4641-4647.
To, W.S., and Midwood, K.S. (2011). Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis & tissue repair 4, 21.

Trevino, S.R., Scholtz, J.M., and Pace, C.N. (2007). Amino acid contribution to protein solubility: Asp, Glu, and Ser contribute more favorably than the other hydrophilic amino acids in RNase Sa. Journal of molecular biology 366, 449-460.

Wang, J.F., Zhang, X.F., and Groopman, J.E. (2001). Stimulation of beta 1 integrin induces tyrosine phosphorylation of vascular endothelial growth factor receptor-3 and modulates cell migration. The Journal of biological chemistry 276, 41950-41957.

Wang, Y., Fei, D., Vanderlaan, M., and Song, A. (2004). Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis 7, 335-345.

Waters, J.D., Sanchez, C., Sahin, A., Futalan, D., Gonda, D.D., Scheer, J.K., Akers, J., Palanichamy, K., Waterman, P., Chakravarti, A., et al. (2012). CT322, a VEGFR-2 antagonist, demonstrates anti-glioma efficacy in orthotopic brain tumor model as a single agent or in combination with temozolomide and radiation therapy. Journal of neuro-oncology 110, 37-48.

Whittaker, C.A., and Hynes, R.O. (2002). Distribution and evolution of von Willebrand/integrin A domains: widely dispersed domains with roles in cell adhesion and elsewhere. Molecular biology of the cell 13, 3369-3387.

Wilhelm, S.M., Adnane, L., Newell, P., Villanueva, A., Llovet, J.M., and Lynch, M. (2008). Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Molecular cancer therapeutics 7, 3129-3140.

Yoo, E.J., Shin, H.S., Kim, S.U., Joo, D.J., Park, J.Y., Choi, G.H., Kim do, Y., Ahn, S.H., Seong, J., Koh, M.J., et al. (2013). Orthotopic liver transplantation after the combined use of locoregional therapy and sorafenib for advanced hepatocellular carcinoma. OncoTargets and therapy 6, 755-759.

Zhou, S., Yang, Y., Yang, Y., Tao, H., Li, D., Zhang, J., Jiang, G., and Fang, J. (2013). Combination Therapy of VEGF-Trap and Gemcitabine Results in Improved Anti-Tumor Efficacy in a Mouse Lung Cancer Model. PloS one 8, e68589.

Zhu, Z., Hattori, K., Zhang, H., Jimenez, X., Ludwig, D.L., Dias, S., Kussie, P., Koo, H., Kim, H.J., Lu, D., et al. (2003). Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity. Leukemia 17, 604-611.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2023-12-31起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw