Abstract：Glioblastoma is one of the most common primary malignant tumors in the central nervous system of adults. Angiogenesis is one of the most important hallmarks of glioblastoma, and vascular endothelial growth factor plays a key role in this process. Bevacizumab is a monoclonal antibody that can specifically prevent the combination of vascular endothelial growth factor and its receptor, thereby inhibiting the formation of tumor blood vessels and normalizing the tumor blood vessels to achieve anti-tumor effect. However, the effects of Bevacizumab in newly diagnosed and recurrent glioblastoma are not as satisfied as expected, furthermore, some cases occurred resistance. This paper reviews the research progress of the mechanism of angiogenesis, mechanism of Bevacizumab and its clinical trails and resistance mechanism in recent years, hoping to summarize the research achievements of anti-vascular therapy, and predict the next research direction.
徐阳 袁凡恩 杨雪 杨吉安 刘宝辉▲ 陈谦学▲. 贝伐单抗在人脑胶质母细胞瘤抗血管生成中的研究进展[J]. 中国医药导报, 2018, 15(15): 43-46,58.
XU Yang YUAN Fan'en YANG Xue YANG Ji'an LIU Baohui▲ CHEN Qianxue▲. Research progress of Bevacizumab in human glioblastoma anti-angiogenesis. 中国医药导报, 2018, 15(15): 43-46,58.
[1] Louis DN，Perry A，Reifenberger G，et al. The 2016 World Health Organization classification of tumors of the central nervous system：a summary [J]. Acta Neuropathol，2016， 131（6）：803-820.
[2] Ostrom QT，Gittleman H，Liao P，et al. CBTRUS statistical report：primary brain and central nervous system tumors diagnosed in the United States in 2010-2014 [J]. Neuro Oncol，2012，14 Suppl 5：v1-v49.
[3] Liu B，Dong H，Lin X，et al. RND3 promotes Snail 1 protein degradation and inhibits glioblastoma cell migration and invasion [J]. Oncotarget，2016，55（12）：612-615.
[4] Chaudhry IH，O'Donovan DG，Brenchley PE，et al. Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas [J]. Histopathology，2001，39（4）：409-415.
[5] Carmeliet P，Jain RK. Molecular mechanisms and clinical applications of angiogenesis [J]. Nature，2011，473（7347）：298-307.
[6] Herbert SP，Huisken J，Kim TN，et al. Arterial-venous segregation by selective cell sprouting：an alternative mode of blood vessel formation [J]. Science，2009，326（5920）：294-298.
[7] Wang R，Chadalavada K，Wilshire J，et al. Glioblastoma stem-like cells give rise to tumour endothelium [J]. Nature，2010，468（7325）：829-833.
[8] Jain RK. Antiangiogenesis strategies revisited：from starving tumors to alleviating hypoxia [J]. Cancer Cell，2014，26（5）：605-622.
[9] Reiss Y，Machein MR，Plate KH，et al. The role of angiopoietins during angiogenesis in gliomas [J]. Brain Pathol，2005， 15（4）：311-317.
[10] Shih AH，Holland EC. Platelet-derived growth factor（PDGF）and glial tumorigenesis [J]. Cancer Lett，2006， 232（2）：139-147.
[11] Abounader，Laterra J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis [J]. Neuro Oncol，2005，7（4）：436-451.
[12] Jayson GC，Kerbel R，Ellis LM，et al. Antiangiogenic therapy in oncology：current status and future directions [J]. Lancet（London，England），2016，388（10043）：518-529.
[13] Pope WB，Xia Q，Paton VE，et al. Patterns of progression in patients with recurrent glioblastoma treated with bevacizumab [J]. Neurology，2011，76（5）：432-437.
[14] Winkler F，Kozin SV，Tong RT，et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation：Role of oxygenation，angiopoietin-1，and matrix metalloproteinases [J]. Cancer Cell，2004，6（6）：553-563.
[15] Jain RK. Normalization of tumor vasculature：an emerging concept in antiangiogenic therapy [J]. Science，2005， 307（5706）：58-62.
[16] Groot JF，Fuller G，Kumar AJ，et al. Tumor invasion after treatment of glioblastoma with bevacizumab：radiographic and pathologic correlation in humans and mice [J]. Neuro Oncol，2010，12（3）：233-242.
[17] Lu KV，Chang JP，Parachoniak CA，et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex [J]. Cancer Cell，2012，22（1）：21-35.
[18] Tompson EM，Frenkel EP，Neuwelt EA，et al. The paradoxical effect of bevacizumab in the therapy of malignant gliomas [J]. Neurology，2011，76（1）：87-93.
[19] Cohen MH，Shen YL，Keegan P，et al. FDA drug approval summary：Bevacizumab（avastin）as treatment of recurrent glioblastoma multiforme [J]. Oncologist，2009，14（11）：1131-1138.
[20] Kreisl TN，Kim L，Moore K，et al. Phase Ⅱ trial of single agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma [J]. Clin Oncol，2009，27（5）：740-745.
[21] Friedman HS，Prados MD，Wen PY，et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma [J]. J Clin Oncol，2009，27（28）：4733-4740.
[22] 李刚，贺世明，高立.贝伐单抗联合化疗治疗复发性恶性胶质瘤：附12例经验[J].中国神经肿瘤杂志，2012， 10（3）：177-183.
[23] 王家祺，梁永，欧阳征，等.贝伐单抗联合替莫唑胺治疗胶质母细胞瘤的临床疗效分析[J].肿瘤药学，2013，3（4）：274-277.
[24] Taal W，Oosterkamp HM，Walenkamp AM，et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma（BELOB trial）：A randomised controlled phase 2 trial [J]. Lancet Oncol，2014，15（9）：943-953.
[25] Lee EQ，Reardon DA，Schiff D，et al. Phase Ⅱ study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma [J]. Neuro Oncol，2015，17（2）：862-867.
[26] Vredenburgh JJ，Desjardins A，Kirkpatrick JP，et al. Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme [J]. Int J Radiat Oncol Biol Phys，2012，82（1）：58-66.
[27] Chinot OL，Wick W，Mason W，et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma [J]. N Engl J Med，2014，370（8）：709-722.
[28] Gilbert MR，Dignam JJ，Armstrong TS，et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma [J]. N Engl J Med，2014，370（8）：699-708.
[29] Herrlinger U，Sch?fer N，Steinbach JP，et al. Bevacizumab plus irinotecan versus temozolomide in newly diagnosed O6-methylguanine-DNA methyltransferase nonmethylated glioblastoma：the randomized GLARIUS trial [J]. J Clin Oncol，2016，34（14）：1611-1619.
[30] Fernando NT，Koch M，Rothrock C，et al. Tumor escape from endogenous，extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors [J]. Clin Cancer Res，2008，14（5）：1529-1539.
[31] Kioi M，Vogel H，Schultz G，et al. Inhibition of vasculogenesis，but not angiogenesis，prevents the recurrence of glioblastoma after irradiation in mice [J]. J Clin Invest，2010，120（3）：694-705.
[32] Lu KV，Bergers G. Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma [J]. CNS Oncol，2013， 2（1）：49-65.
[33] Piao Y，Liang J，Holmes L，et al. Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition [J]. Clin Cancer Res，2013，19（16）：4392-4403.
[34] Tabouret E，Tchoghandjian A，Denicolai E，et al. Recurrence of glioblastoma after radio-chemotherapy is associated with an angiogenic switch to the CXCL12-CXCR4 pathway [J]. Oncotarget，2015，6（13）：11664-11675.
[35] EI Hallani S，Boisselier B，Peglion F，et al. A new alternative mechanism in glioblastoma vascularzation tubular vasculogenic mimicry [J]. Brain，2010，133（4）：973-982.
[36] Park JS，Kim IK，Han S，et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment [J]. Cancer Cell，2016，30（6）：953-967.
[37] Labussière M，Cheneau C，Prahst C，et al. Angiopoietin-2 may be involved in the resistance to bevacizumab in recurrent glioblastoma [J]. Cancer Invest，2016，34（1）：39-44.
[38] Groot J，Liang J，Kong LY，et al. Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma [J]. Oncotarget，2012，3（9）：1036-1048.
2018, Vol. 15 
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