重组人血管内皮抑素对兔VX-2移植瘤腘窝淋巴转移干预的实验研究
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摘要
目的:
(1)观察重组人血管内皮抑素对兔VX-2移植瘤血管及淋巴管生成的影响,探讨其在兔移植瘤生长及腘窝淋巴结转移中的作用。
(2)通过对兔VX-2肌肉移植瘤腘窝淋巴结组织中的新生血管进行微血管密度(MVD)计数及淋巴结铸型,观察淋巴结组织中微血管的形态及分布特点。
方法:
从南华大学实验动物部提取12只新西兰大白兔并在其右后小腿外侧肌肉内植入兔VX-2瘤组织块(1mm~3)建立兔VX-2肌肉移植瘤模型,1周后移植瘤长至直径约3mm大小,并随机分成两组,实验组用恩度0.75mg/Kg耳缘静脉注射抑制兔VX-2肌肉移植瘤生长,对照组用生理盐水耳缘静脉注射进行对照,均持续2周,移植术后每周行1次彩超检查测量瘤体大小及瘤体血供变化,描绘肿瘤生长曲线,计算抑瘤率,用药完成1周后放血处死两组新西兰大白兔,取出两组移植瘤组织及腘窝淋巴结组织进行免疫组化实验,以CD31及LYVE-1分别标记两组瘤组织中微血管及微淋巴管并计数,以CD31标记两组淋巴结组织中微血管并计数,同时检测两组瘤组织中VEGF的表达情况。
采用注射铸型剂ABS(红色)经淋巴结入门小动脉之供血动脉进行淋巴结血管铸型,同时应用淋巴管间接注射技术注射铸型剂ABS(蓝色)观察淋巴结充盈情况。铸型完成后将铸型标本进行腐蚀、修剪,冲洗、切片、干燥、导电等处理,最后扫描电镜下观察和摄相,激光共聚焦下三维重建。
结果:
(1)重组人血管内皮抑素对兔VX-2移植瘤腘窝淋巴结转移率有明显抑制作用(P<0.05);对兔VX-2移植瘤生长体积及瘤体血供也有明显的抑制作用(P<0.05),抑瘤率IR达到了26.22%-29.09%。
(2)实验组兔VX-2移植瘤组织及腘窝淋巴结组织内MVD分别比对照组VX-2移植瘤组织及腘窝淋巴结组织内MVD低(P<0.05)。
(3)实验组兔VX-2移植瘤组织中MLVD比对照组兔VX-2移植瘤组织中MLVD低(P<0.05)。
(4)实验组兔VX-2移植瘤组织中VEGF阳性表达细胞百分数(20.59±3.59)低于对照组兔VX-2移植瘤组织中VEGF阳性表达细胞百分数(30.10±3.89),并有统计学意义(P<0.05)。
(5)对照组VX-2移植瘤细胞VEGF阳性表达水平与兔VX-2移植瘤组织中MVD及MLVD呈正相关(r=0.89,P =0.000;r=0.79,P =0.001),与其腘窝淋巴结组织中MVD也呈正相关(r=0.87,P =0.001);实验组VX-2移植瘤细胞VEGF阳性表达水平与兔VX-2移植瘤组织中MVD及MLVD呈正相关(r=0.85,P =0.003;r=0.81,P =0.006),与其腘窝淋巴结组织中MVD也呈正相关(r=0.82,P =0.001)。
结论:
(1)重组人血管内皮抑素对兔VX-2移植瘤细胞VEGF表达、瘤组织MVD及MLVD水平有抑制作用。提示:重组人血管内皮抑素可抑制微血管和微淋巴管生成。
(2)重组人血管内皮抑素能抑制兔VX-2移植瘤腘窝淋巴结转移,对淋巴结内MVD水平有抑制作用。
Purpose:
(1) Observing rh-endostatin to inhibit Angiogenesis and Lymphangiogenesis of the implanted VX-2 tutor, and discussing the functions of the implanted VX-2 tutor building and the metastasis of popliteal lymph nodes.
(2) Through counting the microvessel density (MVD) of the popliteal lymph nodes issue of implanted VX-2 tumor to rabbits and Lymph nodes matrix ,and observing the shape,distribution characteristics of the microvessel in the popliteal lymph nodes
Methods:
Selected 12 New Zealand white rabbits for the laboratory of the University of Nanhua, and implanted VX-2 rabbit tumor issues(1mm~3)in the muscles of their right hind legs to build the model of implanted VX-2 tutor, and the implanted tumors grown to 3mm in diameter after a week. We divided them randomly into two groups, for the experimental group, we kept using 0.75mg/Kg Endostar intravenous injections in ears vein for two weeks to inhibit the growth of VX-2 implanted tumors, and we used physiological saline intravenous injections for the matched group which also lasted for two weeks. And used color Doppler ultrasound once a week to measure the volume change of the tumors and the change of blood supply within the tumors , then we drew a curve to illustrate the growth of the tumors and calculate the inhibition rate(IR). After using Endostar for a week, we took out the tumor tissues and popliteal lymph nodes of the two group, with the help of immunohistochemistry technology, we marked microvessels and microlymphatic vessels in tumor tissues by CD31 and LYVE-1 respectively and recorded the MVD and MLVD for the two group, and marked microvessels in popliteal lymph node tissues by CD31 for the two group and recorded its MVD, and checked the VEGF in the tumor tissues of the two group.
Adopt an injection with a dose of ABS(red) the lymph nodes introduction of the arterial blood for blood to the nodes with type,indirectly at the same time the lymph application of technology to inject injected with a dose of ABS(blue)observed all nodes. When completed shall form a unit of type, trim, the flushing, slice, dry and conduct electricity,etc. the scanning and camera is focused on laser of reconstruction. the three-dimensional
Results:
(1)Endostar has performed well in inhibiting the metastasis of the popliteal lymph nodes in VX-2 muscles implanted tumors for rabbit(sP<0.05);it has also a remarkable performance in inhibiting the tumor growth and the blood supply inside (all the Ps are below 0.05), and it has achieved IR from 26.22% to 29.09%.
(2)The MVDs in VX-2 rabbit tumor tissues and popliteal lymph node tissues of the matched group are higher than those of the experimental group (P<0.05).
(3)In the matched group, the MLVDs of VX-2 rabbit tumor tissues are higher than those of the experimental group(P<0.05).
(4)The VEGF positive rates of cell percentage in the VX-2 rabbit tumor issues of the matched group(30.10±3.89)are higher than those rates of the experimental group(20.59±3.59), which has a statistical significance(P<0.05).
(5)The VEGF rate of the VX-2 rabbit tumor cell in the matched group correlates positively with the MVDs in the VX-2 rabbit tumor issues and popliteal lymph node tissue(sr=0.89,P =0.000;r=0.79,P =0.001), as well as the MLVDs of the VX-2 tumor tissues,(r=0.87,P =0.001). The VEGF rate of the VX-2 rabbit tumor cell in the experimental group correlates positively with the MVDs in the VX-2 rabbit tumor issues and popliteal lymph node tissues(r=0.85,P =0.003;r=0.81,P =0.006), as well as the MLVDs of the VX-2 tumor tissues,(r=0.82,P =0.001).
Conclusion:
(1) Endostar can inhibit the VEGF positive high rate of VX-2 rabbit implanted tumors, And influence the rate of MVD and MLVD of VX-2 rabbit implanted tumors.
(2) Endostar can inhibit the metastasis of its popliteal lymph node,and influence the rate of MVD of the metastatic lymph node.
(1)观察重组人血管内皮抑素对兔VX-2移植瘤血管及淋巴管生成的影响,探讨其在兔移植瘤生长及腘窝淋巴结转移中的作用。
(2)通过对兔VX-2肌肉移植瘤腘窝淋巴结组织中的新生血管进行微血管密度(MVD)计数及淋巴结铸型,观察淋巴结组织中微血管的形态及分布特点。
方法:
从南华大学实验动物部提取12只新西兰大白兔并在其右后小腿外侧肌肉内植入兔VX-2瘤组织块(1mm~3)建立兔VX-2肌肉移植瘤模型,1周后移植瘤长至直径约3mm大小,并随机分成两组,实验组用恩度0.75mg/Kg耳缘静脉注射抑制兔VX-2肌肉移植瘤生长,对照组用生理盐水耳缘静脉注射进行对照,均持续2周,移植术后每周行1次彩超检查测量瘤体大小及瘤体血供变化,描绘肿瘤生长曲线,计算抑瘤率,用药完成1周后放血处死两组新西兰大白兔,取出两组移植瘤组织及腘窝淋巴结组织进行免疫组化实验,以CD31及LYVE-1分别标记两组瘤组织中微血管及微淋巴管并计数,以CD31标记两组淋巴结组织中微血管并计数,同时检测两组瘤组织中VEGF的表达情况。
采用注射铸型剂ABS(红色)经淋巴结入门小动脉之供血动脉进行淋巴结血管铸型,同时应用淋巴管间接注射技术注射铸型剂ABS(蓝色)观察淋巴结充盈情况。铸型完成后将铸型标本进行腐蚀、修剪,冲洗、切片、干燥、导电等处理,最后扫描电镜下观察和摄相,激光共聚焦下三维重建。
结果:
(1)重组人血管内皮抑素对兔VX-2移植瘤腘窝淋巴结转移率有明显抑制作用(P<0.05);对兔VX-2移植瘤生长体积及瘤体血供也有明显的抑制作用(P<0.05),抑瘤率IR达到了26.22%-29.09%。
(2)实验组兔VX-2移植瘤组织及腘窝淋巴结组织内MVD分别比对照组VX-2移植瘤组织及腘窝淋巴结组织内MVD低(P<0.05)。
(3)实验组兔VX-2移植瘤组织中MLVD比对照组兔VX-2移植瘤组织中MLVD低(P<0.05)。
(4)实验组兔VX-2移植瘤组织中VEGF阳性表达细胞百分数(20.59±3.59)低于对照组兔VX-2移植瘤组织中VEGF阳性表达细胞百分数(30.10±3.89),并有统计学意义(P<0.05)。
(5)对照组VX-2移植瘤细胞VEGF阳性表达水平与兔VX-2移植瘤组织中MVD及MLVD呈正相关(r=0.89,P =0.000;r=0.79,P =0.001),与其腘窝淋巴结组织中MVD也呈正相关(r=0.87,P =0.001);实验组VX-2移植瘤细胞VEGF阳性表达水平与兔VX-2移植瘤组织中MVD及MLVD呈正相关(r=0.85,P =0.003;r=0.81,P =0.006),与其腘窝淋巴结组织中MVD也呈正相关(r=0.82,P =0.001)。
结论:
(1)重组人血管内皮抑素对兔VX-2移植瘤细胞VEGF表达、瘤组织MVD及MLVD水平有抑制作用。提示:重组人血管内皮抑素可抑制微血管和微淋巴管生成。
(2)重组人血管内皮抑素能抑制兔VX-2移植瘤腘窝淋巴结转移,对淋巴结内MVD水平有抑制作用。
Purpose:
(1) Observing rh-endostatin to inhibit Angiogenesis and Lymphangiogenesis of the implanted VX-2 tutor, and discussing the functions of the implanted VX-2 tutor building and the metastasis of popliteal lymph nodes.
(2) Through counting the microvessel density (MVD) of the popliteal lymph nodes issue of implanted VX-2 tumor to rabbits and Lymph nodes matrix ,and observing the shape,distribution characteristics of the microvessel in the popliteal lymph nodes
Methods:
Selected 12 New Zealand white rabbits for the laboratory of the University of Nanhua, and implanted VX-2 rabbit tumor issues(1mm~3)in the muscles of their right hind legs to build the model of implanted VX-2 tutor, and the implanted tumors grown to 3mm in diameter after a week. We divided them randomly into two groups, for the experimental group, we kept using 0.75mg/Kg Endostar intravenous injections in ears vein for two weeks to inhibit the growth of VX-2 implanted tumors, and we used physiological saline intravenous injections for the matched group which also lasted for two weeks. And used color Doppler ultrasound once a week to measure the volume change of the tumors and the change of blood supply within the tumors , then we drew a curve to illustrate the growth of the tumors and calculate the inhibition rate(IR). After using Endostar for a week, we took out the tumor tissues and popliteal lymph nodes of the two group, with the help of immunohistochemistry technology, we marked microvessels and microlymphatic vessels in tumor tissues by CD31 and LYVE-1 respectively and recorded the MVD and MLVD for the two group, and marked microvessels in popliteal lymph node tissues by CD31 for the two group and recorded its MVD, and checked the VEGF in the tumor tissues of the two group.
Adopt an injection with a dose of ABS(red) the lymph nodes introduction of the arterial blood for blood to the nodes with type,indirectly at the same time the lymph application of technology to inject injected with a dose of ABS(blue)observed all nodes. When completed shall form a unit of type, trim, the flushing, slice, dry and conduct electricity,etc. the scanning and camera is focused on laser of reconstruction. the three-dimensional
Results:
(1)Endostar has performed well in inhibiting the metastasis of the popliteal lymph nodes in VX-2 muscles implanted tumors for rabbit(sP<0.05);it has also a remarkable performance in inhibiting the tumor growth and the blood supply inside (all the Ps are below 0.05), and it has achieved IR from 26.22% to 29.09%.
(2)The MVDs in VX-2 rabbit tumor tissues and popliteal lymph node tissues of the matched group are higher than those of the experimental group (P<0.05).
(3)In the matched group, the MLVDs of VX-2 rabbit tumor tissues are higher than those of the experimental group(P<0.05).
(4)The VEGF positive rates of cell percentage in the VX-2 rabbit tumor issues of the matched group(30.10±3.89)are higher than those rates of the experimental group(20.59±3.59), which has a statistical significance(P<0.05).
(5)The VEGF rate of the VX-2 rabbit tumor cell in the matched group correlates positively with the MVDs in the VX-2 rabbit tumor issues and popliteal lymph node tissue(sr=0.89,P =0.000;r=0.79,P =0.001), as well as the MLVDs of the VX-2 tumor tissues,(r=0.87,P =0.001). The VEGF rate of the VX-2 rabbit tumor cell in the experimental group correlates positively with the MVDs in the VX-2 rabbit tumor issues and popliteal lymph node tissues(r=0.85,P =0.003;r=0.81,P =0.006), as well as the MLVDs of the VX-2 tumor tissues,(r=0.82,P =0.001).
Conclusion:
(1) Endostar can inhibit the VEGF positive high rate of VX-2 rabbit implanted tumors, And influence the rate of MVD and MLVD of VX-2 rabbit implanted tumors.
(2) Endostar can inhibit the metastasis of its popliteal lymph node,and influence the rate of MVD of the metastatic lymph node.
引文
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[40] Li G,Sham J,Yang J,et al . Potent antitumor efficacy of an E1B 55kDa-deficient adeno-virus carrying murine endostatin in hepatocelular carcinoma, Int.J [J]. Cancer, 2005,113: 640 -647.
[41] Jacks onMW,Roberts JS,Heckford SE,et al.A potential autocriner ole for vascular endothelial growth factor in p rostate cancer [ J ].Cancer Res,2002,62 (3) : 854-859.
[42]刘福国,周洪美,许建民等.胃癌患者VEGF和Endostatin的表达及其与临床病理特征的关系.山东医药,2009,49(25):11-13.
[43]赵茜,梁小曼,吴秋良等.iNOS、VEGF在乳腺癌中的表达及其与腋窝淋巴结转移的关系.肿瘤防治研究.2004,31 (9 ):545-547.
[44]姚济芬,季银芬,石一复等.微血管密度和血管套及血管内皮生长因子在子宫颈癌中的表达.浙江大学学报(医学版),2003,32(1):206-210.
[1] Folkman J.Tumor angiogenesis : therapeutic implications . N Engl J Med, 1971, 285 (21) : 1182 -1186.
[2] Wei DM, Yan G, Cao XR, et al . Soluble multimer of re-combinantendostatin expressed in E. coli has anti-angiogenesis activity biochemical and biophysical [ J ]. Research Communications, 2006, 345:1398 - 1404.
[3] Kerstin E, Peetra M, Johan D, et al . Angiostatin and endostatin inhibit endothelial cell migration in res -ponse to FGF and VEGF without interfering with specific intracellular signal transductionpathways[ J ]. FEBS Leters, 2003, 536 (3) : 19 - 24.
[4] Tjin RM, Tham S, Satchi-FainaroR, et al.A 27- amino-acid synthetic peptide corresponding to the NH2-terminal Zinc-binding domain of endostatin is responsible for its antitumor activity[ J ]. Cancer Res,2005, 65: 3656 -3663.
[5] Folkman J . Antiangi ogenesis in cancer therapy-endostatin and itsmechanisms of action[ J ].Ex p Cell Res, 2006, 312: 594 - 607.
[6] Eder JP, Supko JG, Clark JW, et al. Phase IClinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily . J Clin Oncol, 2002, 20 (18) : 3772-3784.
[7] Hansma AH,Broxterman HJ, van der Horst, et al. Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections : a phase I and phar- macokinetic study in patients with advanced cancer . Annals of Oncology, 2005, 16 (10) : 1695- 1701.
[8]Herbst RS, Hess KR, Tran HT, et al . PhaseⅠStudy of Recombinant Human Endostatin in Patients With Advanced Solid Tumors . J ClinOncol, 2002, 20 (18) : 3792-3803.
[9] Moschos SJ, Odoux C, Land SR, et al. Endostatin plus interferon-[alpha]2b therapy for metastatic melanoma: a novel combination of antiangiogenic immunomodulatory agents . Melanoma Res,2007, 17 (3) : 193- 200.
[10] KulkeMH,Bergsland EK, Ryan DP, et al. PhaseⅡstudy of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol, 2006, 24:3555-3561.
[11]杨林,王金万,汤仲明等.重组人血管内皮抑制素Ⅰ期临床研究.中国新药杂志, 2004, 13: 548-553.
[12]杨林,王金万,孙燕等.重组人血管内皮抑制素YH-16治疗晚期非小细胞肺癌的临床研究.中华肿瘤杂志, 2006, 28 ( 2 ) :138-141.
[13]刘秀峰,秦叔逵,王琳等.恩度与化疗联合治疗多种晚期恶性肿瘤的临床观察.临床肿瘤学杂志, 2007, 12 (4) : 241-245.
[14]蔡莉,孙立春,杨春雨等.恩度联合化疗治疗中晚期非小细胞肺癌的疗效观察.中国实用内科杂志, 2007, 27 ( 19 ) :1541- 1542.
[15] Dhanalbal M, Ram chandran R,Water man MJ, et al. Endostatin induces endothelial cell apop tosis[ J ]. J Biol Chem, 1999, 274 ( 17) :117-121.
[16] BlochW,Huggel K, Sasaki T, et al. The angiogenesis inhibitor endostatin impairsblood vessel maturation during wound healing [ J ] .FASEB J , 2000, 14 (45 ) : 2373 .
[17] Kitty S, Sylvia H,Marjo MPC, et al,Anginex or endostatin treatment reduces plaque area in collarinduced atherosclerotic plaques of ApoE-/- mice[ J ]. Vascular Pharmacology, 2006, 45: 149 - 159.
[18] Olcay T, Kei S,AnnemarieA, et al.Expression of endostatin in human choroidal neovascular membranes secondary to agerelated macular degeneration[J]. Experimental Eye Research, 2006, 83: 329– 338.
[19] Skovseth DK,VeugerMJ, Sorensen DR, et al. Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo[ J ]. Blood, 2005, 105: 1044– 1051.
[20] Yokoyama Y,Ramakrishnan S . Addition of an aminopeptidase nbinding sequence to human endostatin i mproves inhibiti on of ovarian carcinoma growth[ J ]. Cancer 2005, 104: 321 -331 .
[21] Velde EA,Reijerkerk A,Brandsma D,et al . Early endostatin treatment inhibits meta-static seeding of murine colorectal cancer cells in the liver and their adhesion to endo thelial cells[ J ]. Br . J . Cancer, 2005, 92: 729 - 735.
[22] Graep ler B,Verbeek T, Graeter I, et al. Combined endostatin\sFlt-1anti-angiogenic gene therapy is highly effective in a ratmodel of HCC[ J ]. Hepatology, 2005, 41: 879 - 886.
[23] DutourA,Monteil J, Paraf F, et al. Endostatin cDNA / cationic liposome complexes as a promising therapy to prevent lungmetastases in osteosarcoma: study in a human-like rat orthotopic tumor [ J ]. MolTher, 2005, 11: 311 - 319.
[24] Li G, Sham J, Yang J, et al . Potent antitumor efficacy of an E1B 55kDa-deficient adeno-virus carrying murine endostatin in hepatocelular carcinoma, Int . J [ J ]. Cancer, 2005, 113: 640 - 647.
[25] Subramanian I V, Ghebre R, Ramakrishnan S . Adeno-associated virus-mediated delivery of amutant endostatin suppresses ovarian carcinoma growth in mice[ J ]. Gene Ther, 2005, 12: 30 - 37.
[26] Ga(A|¨) lle Brideau,Markus J . M? kinen, Harri Elamaa, et al.Endostatin Overexp ression inhibits Lymphangiogenesis and Lymph NodeMetastasis in Mice Molecular Biology, Pathobiol -ogy, and Genetics, 2007,67 (24) : 11528 -11535.
[27] Dkhissi F, Lu H, Soria C, et al.Enderstatin exhibits a direct antitumor effect in addition to its antiangiogentic activity in colon cancer cells[ J ]. Hum Gene Ther, 2003, 14: 997 - 1008.
[28] Reis RC, Schuppan D, Barreto AC, et al . Endostatin competes with bFGF for binding to heparin-like glycosam inoglycans . Biochem Biophys Res Commun, 2005, 333 (3) : 976 - 983.
[29] Christie E. Delaney, Br odie T. Weagant, Christina L. Addison.The inhibitory effects of endostatin on endothelial cells are modulated by extracellular matrix.Exp Cell Res, 2006, 312 (13) : 2476 -24 89.
[30] Yuan S, Fu Y,Wang X, et al.Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apop tosis . FASEB,2008, 22 (8) : 2809 -2820.
[31] Huang XY, Chen FH,Li J, et al. Mechanism of fibroblast-like synoviocyte apop tosis induced by recombinant human endostatin in rats with adjuvant arthritis. Anatomical record ,2008, 91 (8) : 1029 - 1037. [32 ] Lu N, Ling Y, Gao Y, et al . Endostar suppresses invasion through downregulating the expression of matrix metalloproteinase-2 /9 in MDA-MB-435 human breast cancercells . Exp BiolMed, 2008, 233(8) : 1013 -1020.
[33] Alex G Richter, Scott McKeown, Sridhar Rathinam, et al. Soluble Endostatin is a novel inhibitor of epithelial repair in I diopathic Pulmonary Fibrosis. Thorax 2009, 64 (2) : 156 - 161.
[34] Judah Folkman. Antiangiogenesis in cancer therapy-endostatin and its mechanisms of action . Experimental Cell Research, 2006, 312(5) : 594– 560.
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[38]郭向阳综述,康骅审校.淋巴管内皮特异性标记物及其在肿瘤淋巴管生成研究中的应用.肿瘤防治研究,2005,32(6):378-379.
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[1] Folkman J.Tumor angiogenesis : therapeutic implications . N Engl J Med, 1971, 285 (21) : 1182 -1186.
[2] Wei DM, Yan G, Cao XR, et al . Soluble multimer of re-combinantendostatin expressed in E. coli has anti-angiogenesis activity biochemical and biophysical [ J ]. Research Communications, 2006, 345:1398 - 1404.
[3] Kerstin E, Peetra M, Johan D, et al . Angiostatin and endostatin inhibit endothelial cell migration in res -ponse to FGF and VEGF without interfering with specific intracellular signal transductionpathways[ J ]. FEBS Leters, 2003, 536 (3) : 19 - 24.
[4] Tjin RM, Tham S, Satchi-FainaroR, et al.A 27- amino-acid synthetic peptide corresponding to the NH2-terminal Zinc-binding domain of endostatin is responsible for its antitumor activity[ J ]. Cancer Res,2005, 65: 3656 -3663.
[5] Folkman J . Antiangi ogenesis in cancer therapy-endostatin and itsmechanisms of action[ J ].Ex p Cell Res, 2006, 312: 594 - 607.
[6] Eder JP, Supko JG, Clark JW, et al. Phase IClinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily . J Clin Oncol, 2002, 20 (18) : 3772-3784.
[7] Hansma AH,Broxterman HJ, van der Horst, et al. Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections : a phase I and phar- macokinetic study in patients with advanced cancer . Annals of Oncology, 2005, 16 (10) : 1695- 1701.
[8]Herbst RS, Hess KR, Tran HT, et al . PhaseⅠStudy of Recombinant Human Endostatin in Patients With Advanced Solid Tumors . J ClinOncol, 2002, 20 (18) : 3792-3803.
[9] Moschos SJ, Odoux C, Land SR, et al. Endostatin plus interferon-[alpha]2b therapy for metastatic melanoma: a novel combination of antiangiogenic immunomodulatory agents . Melanoma Res,2007, 17 (3) : 193- 200.
[10] KulkeMH,Bergsland EK, Ryan DP, et al. PhaseⅡstudy of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol, 2006, 24:3555-3561.
[11]杨林,王金万,汤仲明等.重组人血管内皮抑制素Ⅰ期临床研究.中国新药杂志, 2004, 13: 548-553.
[12]杨林,王金万,孙燕等.重组人血管内皮抑制素YH-16治疗晚期非小细胞肺癌的临床研究.中华肿瘤杂志, 2006, 28 ( 2 ) :138-141.
[13]刘秀峰,秦叔逵,王琳等.恩度与化疗联合治疗多种晚期恶性肿瘤的临床观察.临床肿瘤学杂志, 2007, 12 (4) : 241-245.
[14]蔡莉,孙立春,杨春雨等.恩度联合化疗治疗中晚期非小细胞肺癌的疗效观察.中国实用内科杂志, 2007, 27 ( 19 ) :1541- 1542.
[15] Dhanalbal M, Ram chandran R,Water man MJ, et al. Endostatin induces endothelial cell apop tosis[ J ]. J Biol Chem, 1999, 274 ( 17) :117-121.
[16] BlochW,Huggel K, Sasaki T, et al. The angiogenesis inhibitor endostatin impairsblood vessel maturation during wound healing [ J ] .FASEB J , 2000, 14 (45 ) : 2373 .
[17] Kitty S, Sylvia H,Marjo MPC, et al,Anginex or endostatin treatment reduces plaque area in collarinduced atherosclerotic plaques of ApoE-/- mice[ J ]. Vascular Pharmacology, 2006, 45: 149 - 159.
[18] Olcay T, Kei S,AnnemarieA, et al.Expression of endostatin in human choroidal neovascular membranes secondary to agerelated macular degeneration[J]. Experimental Eye Research, 2006, 83: 329– 338.
[19] Skovseth DK,VeugerMJ, Sorensen DR, et al. Endostatin dramatically inhibits endothelial cell migration, vascular morphogenesis, and perivascular cell recruitment in vivo[ J ]. Blood, 2005, 105: 1044– 1051.
[20] Yokoyama Y,Ramakrishnan S . Addition of an aminopeptidase nbinding sequence to human endostatin i mproves inhibiti on of ovarian carcinoma growth[ J ]. Cancer 2005, 104: 321 -331 .
[21] Velde EA,Reijerkerk A,Brandsma D,et al . Early endostatin treatment inhibits meta-static seeding of murine colorectal cancer cells in the liver and their adhesion to endo thelial cells[ J ]. Br . J . Cancer, 2005, 92: 729 - 735.
[22] Graep ler B,Verbeek T, Graeter I, et al. Combined endostatin\sFlt-1anti-angiogenic gene therapy is highly effective in a ratmodel of HCC[ J ]. Hepatology, 2005, 41: 879 - 886.
[23] DutourA,Monteil J, Paraf F, et al. Endostatin cDNA / cationic liposome complexes as a promising therapy to prevent lungmetastases in osteosarcoma: study in a human-like rat orthotopic tumor [ J ]. MolTher, 2005, 11: 311 - 319.
[24] Li G, Sham J, Yang J, et al . Potent antitumor efficacy of an E1B 55kDa-deficient adeno-virus carrying murine endostatin in hepatocelular carcinoma, Int . J [ J ]. Cancer, 2005, 113: 640 - 647.
[25] Subramanian I V, Ghebre R, Ramakrishnan S . Adeno-associated virus-mediated delivery of amutant endostatin suppresses ovarian carcinoma growth in mice[ J ]. Gene Ther, 2005, 12: 30 - 37.
[26] Ga(A|¨) lle Brideau,Markus J . M? kinen, Harri Elamaa, et al.Endostatin Overexp ression inhibits Lymphangiogenesis and Lymph NodeMetastasis in Mice Molecular Biology, Pathobiol -ogy, and Genetics, 2007,67 (24) : 11528 -11535.
[27] Dkhissi F, Lu H, Soria C, et al.Enderstatin exhibits a direct antitumor effect in addition to its antiangiogentic activity in colon cancer cells[ J ]. Hum Gene Ther, 2003, 14: 997 - 1008.
[28] Reis RC, Schuppan D, Barreto AC, et al . Endostatin competes with bFGF for binding to heparin-like glycosam inoglycans . Biochem Biophys Res Commun, 2005, 333 (3) : 976 - 983.
[29] Christie E. Delaney, Br odie T. Weagant, Christina L. Addison.The inhibitory effects of endostatin on endothelial cells are modulated by extracellular matrix.Exp Cell Res, 2006, 312 (13) : 2476 -24 89.
[30] Yuan S, Fu Y,Wang X, et al.Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apop tosis . FASEB,2008, 22 (8) : 2809 -2820.
[31] Huang XY, Chen FH,Li J, et al. Mechanism of fibroblast-like synoviocyte apop tosis induced by recombinant human endostatin in rats with adjuvant arthritis. Anatomical record ,2008, 91 (8) : 1029 - 1037. [32 ] Lu N, Ling Y, Gao Y, et al . Endostar suppresses invasion through downregulating the expression of matrix metalloproteinase-2 /9 in MDA-MB-435 human breast cancercells . Exp BiolMed, 2008, 233(8) : 1013 -1020.
[33] Alex G Richter, Scott McKeown, Sridhar Rathinam, et al. Soluble Endostatin is a novel inhibitor of epithelial repair in I diopathic Pulmonary Fibrosis. Thorax 2009, 64 (2) : 156 - 161.
[34] Judah Folkman. Antiangiogenesis in cancer therapy-endostatin and its mechanisms of action . Experimental Cell Research, 2006, 312(5) : 594– 560.
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