《安维汀抗血管机制》课件

Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,*,安维汀抗血管生成控制肿瘤机制,抗血管生成是治疗肿瘤的关键因素,在多个肿瘤类型中，血管生成是肿瘤发生的关键驱动因素,1,肿瘤直径,2mm,时，其存活与生长需要独立的血液供应,14,1.Folkman.In:Kufe,Pollock,Weichselbaum,eds.Cancer Medicine(Holland).6th ed.Hamilton,Ontario:BC Decker;2000;2.Bergers,Benjamin.Nat Rev Cancer 2003;3.Folkman.NEJM 1971;4.Folkman.J Natl Cancer Inst 1990,3,VEGF,和其受体相互作用调节血管生成,1,5,，,高,VEGF,水平与不佳的临床预后相关,6,19,1.Ferrara.Endocr Rev 2004;2.Hicklin,Ellis.JCO 2005;3.Baka,et al.Expert Opin Ther Targets 2006;4.Morabito,et al.Oncologist 2006;5.de Vries,et al.Science 1992;6.Bergers,Benjamin.Nat Rev Cancer 2003;7.Jain.Science 2005;8.Gerber,Ferrara.Cancer Res 2005;9.Jain.Nat Med 2001;10.Inoue,et al.Cancer Cell 2002;11.Margolin.Curr Oncol Rep 2002;12.Hu,et al.Am J Pathol 2002,，,1.Hicklin,Ellis.JCO 2005;2.Ferrara.Endocr Rev 2004;3.,Ferrara,et al.Nat Rev Drug Discov 2004;4.Margolin.Curr Oncol Rep 2002;5.,Kaya,et al.Respir Med 2004;6.,Des Guetz,et al.Br J Cancer 2006;7.,O,Byrne,et al.Br J Cancer 2000;8.,Yuan,et al.Int J Cancer(Pred Oncol)2000;9.,Imoto,et al.J Thorac Cardiovasc Surg 1998;10.,Galizia,et al.Clin Cancer Res 2004;11.Ishigami,et al.Br J Cancer 1998;12.,Escudier,et al.Lancet 2007;13.Hu,et al.Am J Pathol 2002;14.Ferrara,Davis-Smyth.Endocr Rev 1997,VEGF,VEGF,受体,促进现有内皮细胞的存活,1,2,68,有助于血管异常化,1,2,6,7,9,VEGF,配体与,VEGF,受体的相互作用是血管生成的关键调节因素,刺激新血管生长,1,2,68,10,增加血管通透性,11,12,4,影响临床疗效的重要原因之一是肿瘤组织血管异常,肿瘤内血管系统排列和机构异常,1.Jain,et al.Nat Med 2001;2.Carmeliet,et al.Nat Rev,Drug Discov 2011,a),异常血管,b),正常血管,c),正常化的肿瘤血管,肿瘤内血管壁的细胞功能也是异常的,1,2,抑制,VEGF,可以逆转,其中部分,异常,血管,1,、,2,贝伐珠单抗精准靶向,VEGF,，抑制血管生成，持续控制肿瘤,1,2,贝伐珠单抗,VEGF,受体,VEGF,1.Avastin Summary of Product Characteristics;2.Presta,et al.Cancer Res 1997;3.Avastin prescribing information,http:/www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf,贝伐珠单抗阻止,VEGF,与受体的结合,1,2,贝伐珠单抗的清除半衰期长（约,20,天），有助于持续控制肿瘤,3,6,对比较传统治疗，贝伐珠单抗的多种作用能提高疗效,120,1.Baluk,et al.Curr Opin Genet Dev 2005;2.Willett,et al.Nat Med 2004;3.O,Connor,et al.Clin Cancer Res 2009;4.Hurwitz,et al.NEJM 2004;5.Sandler,et al.NEJM 2006;6.Escudier,etal.Lancet 2007;7.Miller,et al.NEJM 2007;8.Mabuchi,et al.Clin Cancer Res 2008;9.Wild,et al.Int J Cancer 2004;10.Gerber,Ferrara.Cancer Res 2005;11.Prager,et al.Mol Oncol 2010;12.Yanagisawa,et al.Anti-Cancer Drugs 2010;13.Dickson,et al.Clin Cancer Res 2007;14.Hu,et al.Am J Pathol 2002;,15.Ribeiro,et al.Respirology 2009;16.Watanabe,et al.Hum Gene Ther 2009;17.Mesiano,et al.Am J Pathol 1998;18.Bellati,et al.Invest New Drugs 2010;19.Huynh,et al.JHepatol 2008;20.Ninomiya,et al.J Surg Res2009,现有肿瘤血管系统的,退化,13,抑制,新血管的生长,13,8,对现存血管系统的,抗通透性,1113,7,肿瘤,血,管系统的,退化,临床前证据,1:,治疗开始时加入抗,VEGF,抗体的,重要作用,1,在抗,VEGF,抗体,G6-31,治疗的人结直肠癌移植瘤模型中，采用,微型计算机血管造影,评估体外肿瘤血管系统,G6-31,给药,48,小时内，血管和肿瘤体积明显降低,1,1.O,Connor,et al.Clin Cancer Res 2009,对照,抗,VEGF,Figure reprinted with permission from O,Connor JP,et al.Clin Cancer Res 2009;15:667482,Figure 1B,9,临床前证据,2:,降低,MVD,1,在带有人结肠腺癌,(LS174T),的免疫缺陷小鼠,(SCID),中，研究贝伐珠单抗,*,对,MVD,的作用,1,受试动物接受,0.2mL(492,g/mL),贝伐珠单抗或生理盐水,i.p.,或,i.v.,推注；,在治疗后,6,小时到,11,天的不同时间点进行评估,与对照组相比，抗,VEGF,治疗显著降低,LS174T,肿瘤的血管通透性及血管体积,(p0.05),，血管迅速退化,1.Yuan,et al.PNAS USA 1996,对照,抗,VEGF,治疗,治疗前,3,天,7,天,*,临床前疗效评估采用的是贝伐珠单抗的小鼠替代品,A4.6.1MVD=,微血管密度,Figure reprinted from,Yuan F,et al.PNAS USA 1996;93(25):14765,70.Copyright 2009 National Academy of Sciences,USA,10,抑制新血管生长,临床前证据,1:,延缓肿瘤生长,1,人结肠癌,(SW620),植入小鼠的移植瘤模型,1,每周,2,次给予抗,VEGF,抗体，持续,3,周，或直至研究结束,抗,VEGF,抗体,B20-4.1,和,B20-4.1.1,作为贝伐珠单抗的替代品,与对照组相比，抗,VEGF,治疗延缓的肿瘤生长,当治疗持续较长时间时，肿瘤抑制更有效,与对照组相比，生存期显著延长,(p0.05),1.Bagri,et al.Clin Cancer Res 2010,Figures reprinted with permission from Bagri A,et al.Clin Cancer Res 2010;16:3887900,Figures 2A and B,EOS=,研究结束,*,持续,3,周,持续至研究结束,长期的抗,VEGF,治疗降低肿瘤生长,接受更长时间抗,VEGF,治疗的动物存活时间更长,平均肿瘤体积,(mm3),短期抗,VEGF*,长期抗,VEGF,天,研究中存活的动物,(%),对照,天,对照,12,抗现存血管系统的通透性,降低现存血管的通透性，,带来,的,抗肿瘤作用,1,2,血管直径降低,4,组织间隙液压下降,13,血管通透性下降,5,6,1.Willett,et al.Nat Med 2004;2.Gerber,Ferrara.Cancer Res 2005;3.,Tobelem.Targ Oncol 2007;,4.Yuan,et al.PNAS USA 1996;5.Dickson,et al.Clin Cancer Res 2007