内皮抑素与阿霉素联合碘油栓塞治疗肝癌的多普勒超声监测
|
摘要
目的通过二维超声、彩色多普勒超声及免疫组化方法观察兔肝移植瘤生长情况及肝动脉内皮抑素碘油栓塞对兔瘤生长、血管形成、血流动力学及微血管密度的影响。
材料与方法1.健康纯种新西兰大白兔32只,采用开腹肿瘤组织块直接种植法将1-2块1mm~3大小瘤组织植入兔肝左或右中央叶。超声动态观察瘤块生长情况及形态变化,待肝内肿块长至1-2cm时备用。2.VX2种植瘤模型兔30只,随机分为3组,每组10只。对照组:经导管注入10ml生理盐水;TACE组:2mg/kg阿霉素与0.2ml/kg超液态碘油充分混匀后经微导管缓慢注入;抗血管生成组:2mg/kg阿霉素、0.2ml/kg超液态碘油和2mg&g内皮抑素充分混匀后经微导管缓慢注入。3.采用二维超声监测肿瘤的体积变化,计算肿瘤生长率,以肿瘤体积变化对时间绘制生长曲线。于肝VX2瘤介入治疗前、治疗后4d、治疗后7d行超声检查,观察肿瘤周边及内部血流分布,记录瘤体多普勒血流参数,测定肝动脉最大血流速度(Vmax)、阻力指数(RI)和门静脉平均血流速度(V)。4.治疗后7天左右处死瘤兔,大体观察肝脏肿瘤表面,测量瘤块大小,剖面观察肿瘤内部坏死灶,分别行组织病理学检查(大体、光镜),免疫组化方法检测肿瘤组织MVD,图像分析软件两人分别计数各组MVD。比较超声血流分级与MVD之间的相关性。
结果1.治疗前各组肿瘤体积无统计学差异(P＞0.05)。治疗后抗血管生成组肿瘤生长率(-20.40±36.1)明显低于对照组(269.86±148.9)(P＜0.01)。2.治疗前超声显示各组荷瘤兔肝动脉最大血流速度呈动态变化,随着肿块的增大而增大。治疗后对照组(41.16±6.65)与抗血管生成组肝动脉最大血流速度(26.17±7.94)比较极显著性降低(P＜0.01),与TACE组(32.72±5.31)比较无明显差异(P＞0.05)。治疗后抗血管生成组阻力指数(0.45±0.10)与对照组(0.35±0.06)比较明显增大(P＜0.05),与TACE组(0.37±0.07)相比无明显差异(P＞0.05)。门静脉平均血流速度各组比较无明显变化(P＞0.05)。3.治疗前彩色及能量多普勒显示各组兔肝移植瘤周边及内部血流信号丰富,治疗后彩色和能量多普勒超声显示抗血管生成组7只荷瘤兔瘤内及瘤周血流信号消失,3只肿块中心及周边尚有点状或短细线状血流信号检出,与其他组相比,肿瘤供血明显减少。4.抗血管生成组MVD表达水平(57.00±13.26)较对照组(80.00±17.14)与TACE组(84.22±16.45)极显著降低(P＜0.01)。超声血流分级0、Ⅰ、Ⅱ、Ⅲ级分别为12例、8例、6例、4例,对应MVD值分别为75.6±16.77、76.00±29.85、68.4±12.48、80.2±21.49,四组之间比较无统计学差异。
结论1.TACE能使VX2肿瘤生长明显受到抑制、体积缩小。内皮抑素联合TACE不但能使肿瘤生长受到明显抑制,还能够影响肿瘤血管形成,使微血管数目明显减少。2.彩色多普勒超声是监测TACE术后疗效的一种便捷、有效的影像学方法。
Objective To investigate the effect of TACE with endostatin and Lipiodol on growth,angiogenesis,and MVD expression of rabbit VX2 hepatic tumor by two-dimention sonography,color Doppler flow(power) imaging and immunohistochemistry method.
Material and methods 1.Thirty-two New Zealand white healthy rabbits,2 pieces of 1mm~3 fragment of VX2 carcinoma were inoculated into the sub-capsule of the left or right hepatic central lobe via laparotomy.Morphologic changes of hepatic tumors were observed by ultrasonography.The embolization was performed when the diameter of tumors grew to about 1-2cm in models.2.30 New Zealand white rabbit models were divided into 3 groups randomly,10 rabbits in each group. ADM-lipiodol,endostatin(2mg/kg) combined with ADM-lipiodol and 0.9%saline about 10ml were perfused respectively via hepatic artery in different groups of VX2 tumor-bearing rabbit models,2mg/kg adriamycin in each 0.2ml/kg lipiodol emulsion was injected.3.Used 2-D ultrasound to observe the volume change of tumors, calculate the rate of growth and write the growth curve of tumors in rabbit different model groups.Taking CDPI to observe the characteristics of blood flow in tumors. To observe and assay the disposition of blood and the hemodynamics parameters of VX2 tumors such as the maximal velocity and the resistant index of hepatic artery, the velocity of portal vein respectively by color Doppler flow imaging before treatment and on the 4th and 7th day after treatment.4.Pathological tissue was obtained from rabbit models at the time of killing,on the 7th day after therapy.The hepatocarcinoma tissue was observed by naked eye,hematoxylin and eosin stained and immunohistochemistry stained respectively.Measured the diameter of tumor. The data of MVD expression were calculated by two person.The change of tumor morphology and tumor microvessel density was observed by microscope.Compared the correlation of blood flow grade and MVD.
Results 1.The changes were not significant the tumors' volume of models before therapy.After therapy,the tumors' growth rate of endostatin combined with ADM-lipiodol group(-20.4±36.1) was significantly lower than that of control group(269.86±148.9)(P＜0.01).2.Observed by Doppler ultrasonography,the maximal velocity of hepatic artery in group endostatin-AL(26.17±7.94) was lower than that of control group(41.16±6.65)(P＜0.05),not significant compared with that of group AL(32.72±5.31)(P＞0.05).The resistant index of hepatic artery in group endostatin-AL(0.45±0.10) was higher than that of control group(0.35±0.06) (P＜0.05),the change of resistant index of hepatic artery in group AL(0.37±0.07) was not significant compared with that of group endostatin-AL.There was not significant change in the velocities of portal vein in rabbit model groups(P＞0.05).3. Observed by CDFI and CDPI,the blood flow signals para-tumors and intra-tumors significantly were richer before perfusion,became less(3/10) and even disappearing completely(7/10) after embolization.The tumor blood-flow block were more obviously in the group of endostatin-AL than that of other groups.4.The tumors' MVD of endostatin-AL group(57.00±13.26) was significantly lower than that of AL group(84.22±16.45) and control group(80.00±17.14)(P＜0.01).The cases of blood flow grade 0、Ⅰ、Ⅱ、Ⅲis 12、8、6、4 respectively,the corresponding of MVD was 75.6±16.77,76.00±29.85,68.4±12.48 and 80.2±21.49,but there was no statistically significant difference(P＞0.05).
Conclusion 1.TACE can inhibit the growth of the implanted VX2 tumor,but maybe have no effect on metastasis;TACE combined with endostatin treatment not only can inhibit the growth of the implanted tumor but also can inhibit its metastasis.2.Color Doppler sonography is a effective and convenient imaging method for observation the effect of transcatheter arterial chemoembolization on hepatocellular carcinoma.
材料与方法1.健康纯种新西兰大白兔32只,采用开腹肿瘤组织块直接种植法将1-2块1mm~3大小瘤组织植入兔肝左或右中央叶。超声动态观察瘤块生长情况及形态变化,待肝内肿块长至1-2cm时备用。2.VX2种植瘤模型兔30只,随机分为3组,每组10只。对照组:经导管注入10ml生理盐水;TACE组:2mg/kg阿霉素与0.2ml/kg超液态碘油充分混匀后经微导管缓慢注入;抗血管生成组:2mg/kg阿霉素、0.2ml/kg超液态碘油和2mg&g内皮抑素充分混匀后经微导管缓慢注入。3.采用二维超声监测肿瘤的体积变化,计算肿瘤生长率,以肿瘤体积变化对时间绘制生长曲线。于肝VX2瘤介入治疗前、治疗后4d、治疗后7d行超声检查,观察肿瘤周边及内部血流分布,记录瘤体多普勒血流参数,测定肝动脉最大血流速度(Vmax)、阻力指数(RI)和门静脉平均血流速度(V)。4.治疗后7天左右处死瘤兔,大体观察肝脏肿瘤表面,测量瘤块大小,剖面观察肿瘤内部坏死灶,分别行组织病理学检查(大体、光镜),免疫组化方法检测肿瘤组织MVD,图像分析软件两人分别计数各组MVD。比较超声血流分级与MVD之间的相关性。
结果1.治疗前各组肿瘤体积无统计学差异(P＞0.05)。治疗后抗血管生成组肿瘤生长率(-20.40±36.1)明显低于对照组(269.86±148.9)(P＜0.01)。2.治疗前超声显示各组荷瘤兔肝动脉最大血流速度呈动态变化,随着肿块的增大而增大。治疗后对照组(41.16±6.65)与抗血管生成组肝动脉最大血流速度(26.17±7.94)比较极显著性降低(P＜0.01),与TACE组(32.72±5.31)比较无明显差异(P＞0.05)。治疗后抗血管生成组阻力指数(0.45±0.10)与对照组(0.35±0.06)比较明显增大(P＜0.05),与TACE组(0.37±0.07)相比无明显差异(P＞0.05)。门静脉平均血流速度各组比较无明显变化(P＞0.05)。3.治疗前彩色及能量多普勒显示各组兔肝移植瘤周边及内部血流信号丰富,治疗后彩色和能量多普勒超声显示抗血管生成组7只荷瘤兔瘤内及瘤周血流信号消失,3只肿块中心及周边尚有点状或短细线状血流信号检出,与其他组相比,肿瘤供血明显减少。4.抗血管生成组MVD表达水平(57.00±13.26)较对照组(80.00±17.14)与TACE组(84.22±16.45)极显著降低(P＜0.01)。超声血流分级0、Ⅰ、Ⅱ、Ⅲ级分别为12例、8例、6例、4例,对应MVD值分别为75.6±16.77、76.00±29.85、68.4±12.48、80.2±21.49,四组之间比较无统计学差异。
结论1.TACE能使VX2肿瘤生长明显受到抑制、体积缩小。内皮抑素联合TACE不但能使肿瘤生长受到明显抑制,还能够影响肿瘤血管形成,使微血管数目明显减少。2.彩色多普勒超声是监测TACE术后疗效的一种便捷、有效的影像学方法。
Objective To investigate the effect of TACE with endostatin and Lipiodol on growth,angiogenesis,and MVD expression of rabbit VX2 hepatic tumor by two-dimention sonography,color Doppler flow(power) imaging and immunohistochemistry method.
Material and methods 1.Thirty-two New Zealand white healthy rabbits,2 pieces of 1mm~3 fragment of VX2 carcinoma were inoculated into the sub-capsule of the left or right hepatic central lobe via laparotomy.Morphologic changes of hepatic tumors were observed by ultrasonography.The embolization was performed when the diameter of tumors grew to about 1-2cm in models.2.30 New Zealand white rabbit models were divided into 3 groups randomly,10 rabbits in each group. ADM-lipiodol,endostatin(2mg/kg) combined with ADM-lipiodol and 0.9%saline about 10ml were perfused respectively via hepatic artery in different groups of VX2 tumor-bearing rabbit models,2mg/kg adriamycin in each 0.2ml/kg lipiodol emulsion was injected.3.Used 2-D ultrasound to observe the volume change of tumors, calculate the rate of growth and write the growth curve of tumors in rabbit different model groups.Taking CDPI to observe the characteristics of blood flow in tumors. To observe and assay the disposition of blood and the hemodynamics parameters of VX2 tumors such as the maximal velocity and the resistant index of hepatic artery, the velocity of portal vein respectively by color Doppler flow imaging before treatment and on the 4th and 7th day after treatment.4.Pathological tissue was obtained from rabbit models at the time of killing,on the 7th day after therapy.The hepatocarcinoma tissue was observed by naked eye,hematoxylin and eosin stained and immunohistochemistry stained respectively.Measured the diameter of tumor. The data of MVD expression were calculated by two person.The change of tumor morphology and tumor microvessel density was observed by microscope.Compared the correlation of blood flow grade and MVD.
Results 1.The changes were not significant the tumors' volume of models before therapy.After therapy,the tumors' growth rate of endostatin combined with ADM-lipiodol group(-20.4±36.1) was significantly lower than that of control group(269.86±148.9)(P＜0.01).2.Observed by Doppler ultrasonography,the maximal velocity of hepatic artery in group endostatin-AL(26.17±7.94) was lower than that of control group(41.16±6.65)(P＜0.05),not significant compared with that of group AL(32.72±5.31)(P＞0.05).The resistant index of hepatic artery in group endostatin-AL(0.45±0.10) was higher than that of control group(0.35±0.06) (P＜0.05),the change of resistant index of hepatic artery in group AL(0.37±0.07) was not significant compared with that of group endostatin-AL.There was not significant change in the velocities of portal vein in rabbit model groups(P＞0.05).3. Observed by CDFI and CDPI,the blood flow signals para-tumors and intra-tumors significantly were richer before perfusion,became less(3/10) and even disappearing completely(7/10) after embolization.The tumor blood-flow block were more obviously in the group of endostatin-AL than that of other groups.4.The tumors' MVD of endostatin-AL group(57.00±13.26) was significantly lower than that of AL group(84.22±16.45) and control group(80.00±17.14)(P＜0.01).The cases of blood flow grade 0、Ⅰ、Ⅱ、Ⅲis 12、8、6、4 respectively,the corresponding of MVD was 75.6±16.77,76.00±29.85,68.4±12.48 and 80.2±21.49,but there was no statistically significant difference(P＞0.05).
Conclusion 1.TACE can inhibit the growth of the implanted VX2 tumor,but maybe have no effect on metastasis;TACE combined with endostatin treatment not only can inhibit the growth of the implanted tumor but also can inhibit its metastasis.2.Color Doppler sonography is a effective and convenient imaging method for observation the effect of transcatheter arterial chemoembolization on hepatocellular carcinoma.
引文
[1]Hansen S,Sorensen FB,Vach W,et al.Microvessel density compared with the Chalkley count in a prognostic study of angiogenesis in breast cancer patients[J].Histopathology,2004,44(5):428-436.
[2]Mineo TC,Ambroqi V,Baldi A,et al.Prognostic impact of VEGF,CD31,CD34,CD105 expression and tumour vessel invasion after radical surgery for IB-IIA non-small cell lung cancer[J].J Clin Pathol.2004,57(6):591-597.
[3]Pettersson H.Arterial collaterals in intrahepatic arterial occlusion[J].Acta Radiol Diagn(Stockh),1975,16(4):401-406.
[4]Mugitani T,Taniguchi H,Takada A,et al.TNP-470 inhibits collateralization to complement the anti-tumor effect of hepatic artery ligation[J].Br J Cancer,1998,77(4):638-642.
[5]Hsu HC,Wei TC,Tsang YM,et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic arterial embolization[J].Cancer,1986,57(6):1184-1191.
[6]Swistel AJ,Bading JR,Raaf JH,et al.Intraarterial versus intravenous adriamycin in the rabbit VX-2 tumor system[J].Cancer,1984,53(6):1397-1404.
[7]Mugitani T,Taniguchi H,Takada A,et al.TNP-470 inhibits collateralization to complement the anti-tumour effect of hepatic artery ligation[J].Br J Cancer,1998,77(4):638-642.
[8]曹玮,王执民,张洪新,等.兔VX2肝癌模型的移植方式及生长特性的研究[J].实用放射学杂志,2003.19(2):97-99.
[9]贺声,曹铁生.段云友.兔肝VX2瘤血供超声显示与肿瘤增殖活性的关系[J].中国医学影像技术.1999,15(12):995-998.
[10]Rak JW.St Croix DB.Kerbel RS.et al.Consequences of angiogenesis for tumor progession,netastasis and cancer therapy[J].Anti Cancer Drugs.1995,6(1):3-18.
[11]Augustin HG.Antiangiogenic tumor therapy:will it work[J].Trends Pharmacol Sci,1998,19(6):216-222.
[12]李欣,郑传胜,冯敢生,等.肿瘤血管生成及影像学在其中的应用[J].国外医学 临床放射学分册,2000,5:293-297.
[13]曹玮,王执民,梁志会.等.血管生成抑制剂TNP-470与碘化油混合栓塞肝癌的实验研究[J].世界华人消化杂志,2000,8(6):629-632.
[14]Liou TC,Shih SC,Kao CR,et al.Pulmonary metastasis of hepatocellular carcinoma associated with transarterial chemoembolization[J].Hepatology,1995,23(5):563-568.
[15]Boix L,Bruix J,Castells A,et al.Circulating mRNA for alphafetoprotein in patients with hepatocellular carcinoma.Evidence of tumor dissemination after transarterial embolization[J].Hepatolog,1996,24(2):349-350.
[16]Adachi E,Matsumata T,Nishizaki T,et al.Effects of preoperative transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma[J].Cancer,1993,72(12):3593.
[17]O'Reilly MS,Boehm T,Shing Y,et al.Endostatin:an endogenous inhibitor of angiogenesis and tumor growth[J].Cell,1997,88(2):277-285.
[18]Hohenester E,Sasaki T,Olsen BR,et al.Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution[J].EMBO Journal,1998,17(6):1656-1664.
[19]Sasaki T,Larsson H,Kreuger J,et al.Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin[J].E MBO J,1999,18(22):6240-6248
[20]Yamaguchi N,Anand-Apte B,Lee M,et al.Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding[J].E MBO J,1999,18(16):4414-4423.
[21]Dhanabal M,Ramchandran R,Waterman MJ,et al.Endostatin induces endothelial cell apoptosis[J].Journal of Biological Chemistry,1999.274(17):11721-11726.
[22]Dhanabal M.Ramchandran R,Volk R,et al.Endostatin:yeast production,mutants,and antitumor effect in renal cell carcinoma[J].Cancer Research, 1999,59(1):189-197.
[23]Dhanabal M,Volk R,Ramchandran R,et al.Cloning,expression,and in vitro activity of humanendostatin[J].Biochemical and Biophysical Research Communications,1999,258(2):345-352.
[24]Dhanabal M,Ramchandran R,Volk R,et al.Endostatin:yeast production,mutants,and antitumor effect in renal cell carcinoma[J].Cancer Research,1999,59(1):189-197.
[25]Lee SJ,Jang JW,Kim YM,et al.Endostatin binds to the catalytic domain of matrix metalloproteinase-2[J].FEBS Letters,2002,519(1-3):147-152.
[26]Dixelius J,Cross M,Matsumoto T,et al.Endostatin regulates endothelial cell adhesion and cytoskeletal organization[J].Cancer Res,2002,62(7):1944-1947.
[27]Yamaguchi N,Anand-Apte B,Lee M,et al.Endostatin inhibts VEGF-induced endothelial cell migration and tumor growth independently of zinc binding[J].EMBO J,1999,18(16):4414-4423.
[28]Kubota K,Hisa N,Nishikawa T,et al.Evaluation of hepatocellular carcinoma after treatment with transcatheter arterial chemoembolization:comparison of Lipiodol-CT,power Doppler sonography,and dynamic MRI[J].Abdom Imaging,2001,26(2):184-190.
[29]Castrucci M,Sironi S,De Cobelli F,et al.Plain and gadolinium DYPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization[J].Abdominial Imaging,1996,21(6):488-494.
[30]肖运平.肝细胞癌介入术后疗效的影像学评价[J].中国医学影像技术,2006,22(9):1438-1441.
[31]Tanaka k,Inoue S,Numata K,et al.Color Doppler sonography of hepatocellular carcinoma before and after treatment by transcatheter arterial embolization[J].AJR Am J Roentgenol.1992,158(3):541-546.
[32]贺声,曹铁生,段云友.肝癌血管超声观测的临床病理学意义[J].国外医学肿瘤学分册,1999.26(4):237-239.
[33]Vaupl P.Kallinowski F.Okunieff P.Blood flow,oxygen and nutrient supply and metabolic microenvironment of human tumors:a review[J].Cancer Res,1989,49(23):6449-6465.
[34]Tanaka k,Inoue S,Numata K,et al.Color Doppler sonography of hepatocellular carcinoma before and after treatment by transcatheter arterial embolization[J].Am J Roentgenol,1992,158(3):541-546.
[35]韩增辉,钱蕴秋,王全华.能量多普勒:一种新的多普勒显像技术[J].中国超声医学杂志,1996,12(4):58-60.
[36]Sumi S,Yamashita Y,Mitsuzaki K,et al.Power Doppler sonography assessment of tumor recurrence after chemoembolization therapy for hepatocellular carcinoma[J].AIR,1999,172(1):67-71.
[37]Hosoki T,Mitomo M,Chor S,et al.Visualization of tumor vessels in HCC:Power Doppler compared with color Doppler and angiography[J].Acta-Radiol,1997,38(3):422-427.
[38]Fidler IJ.The biology of human cancer metastasis[J].Acta Oncologica,1991,30(6):669-675.
[39]Follkman J.Seminars in Medicine of the Beth Israel Hospital,Boston.Clinical applications of research on angiogenesis[J].N Engl J Med,1995,333(26):1757-1763.
[40]Follkman J.What is the evidence that tumors are angiogenesis dependent?[editorial].J Natl Cancer Inst,1990,82(1):4-6.
[41]Cockerill GW,Gamble JR,Vadas MA.Angiogenesis:models and modulators[J]Int Rev Cytol,1995,159:113-160.
[42]Dvorak HF,Nagy JA,Feng D.et al.Vascular permeability factor/vascular endothelial growth factor,microvascular hyperpermeability,and angiogenesis[J].Am J Pathol,1995,146(5):1029-1039.
[43]Baillie CT,Winslet MC,Bradley NJ.Tumour vasculature-a potential therapeutic target[J].Br J Cancer,1995,72(2):257-267.
[44]Park YN,Kim YB,Yang KM.et al.Increased expression of vascular endothelial growth factor and angiogenesis in the early stage multistep hepatocarcinogenesis[J].Arch Pathol Lab Med.2000.124(7):1061-1065.
[45]Potgens AJ,Westphal HR,De waal RM,et al.The role of vascular permeability factor and basic fibroblast growth factor in tumor angiogenesis[J].Biol chem.Hoppe Seyler,1995,376(2):57-70.
[46]Luiten RM,Fleuren GJ,Warnoar SO,et al.Target-specific activation of mast cells by immunoglobulin E reactive with renal cell carcinoma-associated antigen[J].Lab Invest,1996,74(2):467-475.
[47]Yamazaki,Abe S,Takekawa H,et al.Tumor angiogenesis in human lung adenocarcinoma[J].Cancer,1994,74(4):2245-2250.
[48]Martin L,Holcombe C,Renshaw C,et al.Standardising the counting technique of neovascularization in invasive breast cancer[J].Breast Cancer Res&Treat,1996,37(5):34-54.
[49]Kumar H,Heer K,Lee PW,et al.Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer[J].Clin Cancer Res,1998,4(5):1279-1285.
[50]Jubb AM,Hurwitz HI,Bai W et al.Impact of vascular endothelial growth factor-A expression,thrombospondin-2 expression,and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer[J].J Clin Oncol,2006,24(2):217-227.
[51]唐震,巫北海,韩丹.CT扫描肝细胞癌边缘肿瘤血管与肿瘤转移和预后的关系[J].实用放射学杂志,2002,18(6):464-466.
[52]Weidner N,Semple JP,Welch WR,et al.Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma[J].N Engl J Med,1991,324(1):1-8.
[53]Dales JP,Garcia S,Carpentier S,et al.Prediction of metastasis risk(11 year follow-up) using VEGF-R1,VEGF-R2,Tie-2/Tek and CD105 expression in breast cancer(n=905)[J].Br J Cancer,2004,90(6):1216-1221.
[54]Dales JP,Garcia S,Carpentier S,et al.Long-term prognostic significance of neoangiogenesis in breast carcinomas:comparison of Tie-2/Tek,CD105,and CD31 immunocytochemical expression[J].Hum Pathol,2004,35(2):176-183.
[55]徐辉,王滨,高志芹,等.肝动脉化疗栓塞对肿瘤新生血管生成的影响[J]. 实用放射学杂志,2004,20(7):620-622.
[56]廖晓锋,易继林,杨志芳,等.肝细胞癌化疗栓塞后肿瘤微血管密度的变化[J].华中科技大学学报(医学版),2002,31(5):544-546.
[57]Liao XF,Yi JL,Li XR,et al.Angiogenesis in rabbit hepatic tumor after transcatheter arterial embolization[J].World J Gastroenterol,2004,10(13):1885-1889.
[58]Weidner N,Folkman J,Pozza F,et al.Tumor angiogenesis:a new significant independent prognostic indicator in early-stage breast carcinoma[J].J Natl Cancer Inst,1992,84(24):1875-1887.
[59]Tanaka K,Inoue S,Numata K,et al.Color doppler sonography of hepatocellular carcinoma before and after treatment by transcatheter arterial embolization[J].AJR,1992,158(3):541-546.
[60]李建国.原发性肝癌的超声诊断现状与展望[J].中国医学影像技术,1998,14(14):466-467.
[61]罗葆明,文艳玲,潘景升,等.能量谐波成像声学造影在肝动脉栓塞治疗中的应用[J].中国超声医学杂志,2000,16(5):352.
[62]徐智章 主编.现代腹部超声诊断学[M].北京:科学出版社,2001:32-33.
[2]Mineo TC,Ambroqi V,Baldi A,et al.Prognostic impact of VEGF,CD31,CD34,CD105 expression and tumour vessel invasion after radical surgery for IB-IIA non-small cell lung cancer[J].J Clin Pathol.2004,57(6):591-597.
[3]Pettersson H.Arterial collaterals in intrahepatic arterial occlusion[J].Acta Radiol Diagn(Stockh),1975,16(4):401-406.
[4]Mugitani T,Taniguchi H,Takada A,et al.TNP-470 inhibits collateralization to complement the anti-tumor effect of hepatic artery ligation[J].Br J Cancer,1998,77(4):638-642.
[5]Hsu HC,Wei TC,Tsang YM,et al.Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic arterial embolization[J].Cancer,1986,57(6):1184-1191.
[6]Swistel AJ,Bading JR,Raaf JH,et al.Intraarterial versus intravenous adriamycin in the rabbit VX-2 tumor system[J].Cancer,1984,53(6):1397-1404.
[7]Mugitani T,Taniguchi H,Takada A,et al.TNP-470 inhibits collateralization to complement the anti-tumour effect of hepatic artery ligation[J].Br J Cancer,1998,77(4):638-642.
[8]曹玮,王执民,张洪新,等.兔VX2肝癌模型的移植方式及生长特性的研究[J].实用放射学杂志,2003.19(2):97-99.
[9]贺声,曹铁生.段云友.兔肝VX2瘤血供超声显示与肿瘤增殖活性的关系[J].中国医学影像技术.1999,15(12):995-998.
[10]Rak JW.St Croix DB.Kerbel RS.et al.Consequences of angiogenesis for tumor progession,netastasis and cancer therapy[J].Anti Cancer Drugs.1995,6(1):3-18.
[11]Augustin HG.Antiangiogenic tumor therapy:will it work[J].Trends Pharmacol Sci,1998,19(6):216-222.
[12]李欣,郑传胜,冯敢生,等.肿瘤血管生成及影像学在其中的应用[J].国外医学 临床放射学分册,2000,5:293-297.
[13]曹玮,王执民,梁志会.等.血管生成抑制剂TNP-470与碘化油混合栓塞肝癌的实验研究[J].世界华人消化杂志,2000,8(6):629-632.
[14]Liou TC,Shih SC,Kao CR,et al.Pulmonary metastasis of hepatocellular carcinoma associated with transarterial chemoembolization[J].Hepatology,1995,23(5):563-568.
[15]Boix L,Bruix J,Castells A,et al.Circulating mRNA for alphafetoprotein in patients with hepatocellular carcinoma.Evidence of tumor dissemination after transarterial embolization[J].Hepatolog,1996,24(2):349-350.
[16]Adachi E,Matsumata T,Nishizaki T,et al.Effects of preoperative transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma[J].Cancer,1993,72(12):3593.
[17]O'Reilly MS,Boehm T,Shing Y,et al.Endostatin:an endogenous inhibitor of angiogenesis and tumor growth[J].Cell,1997,88(2):277-285.
[18]Hohenester E,Sasaki T,Olsen BR,et al.Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution[J].EMBO Journal,1998,17(6):1656-1664.
[19]Sasaki T,Larsson H,Kreuger J,et al.Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin[J].E MBO J,1999,18(22):6240-6248
[20]Yamaguchi N,Anand-Apte B,Lee M,et al.Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding[J].E MBO J,1999,18(16):4414-4423.
[21]Dhanabal M,Ramchandran R,Waterman MJ,et al.Endostatin induces endothelial cell apoptosis[J].Journal of Biological Chemistry,1999.274(17):11721-11726.
[22]Dhanabal M.Ramchandran R,Volk R,et al.Endostatin:yeast production,mutants,and antitumor effect in renal cell carcinoma[J].Cancer Research, 1999,59(1):189-197.
[23]Dhanabal M,Volk R,Ramchandran R,et al.Cloning,expression,and in vitro activity of humanendostatin[J].Biochemical and Biophysical Research Communications,1999,258(2):345-352.
[24]Dhanabal M,Ramchandran R,Volk R,et al.Endostatin:yeast production,mutants,and antitumor effect in renal cell carcinoma[J].Cancer Research,1999,59(1):189-197.
[25]Lee SJ,Jang JW,Kim YM,et al.Endostatin binds to the catalytic domain of matrix metalloproteinase-2[J].FEBS Letters,2002,519(1-3):147-152.
[26]Dixelius J,Cross M,Matsumoto T,et al.Endostatin regulates endothelial cell adhesion and cytoskeletal organization[J].Cancer Res,2002,62(7):1944-1947.
[27]Yamaguchi N,Anand-Apte B,Lee M,et al.Endostatin inhibts VEGF-induced endothelial cell migration and tumor growth independently of zinc binding[J].EMBO J,1999,18(16):4414-4423.
[28]Kubota K,Hisa N,Nishikawa T,et al.Evaluation of hepatocellular carcinoma after treatment with transcatheter arterial chemoembolization:comparison of Lipiodol-CT,power Doppler sonography,and dynamic MRI[J].Abdom Imaging,2001,26(2):184-190.
[29]Castrucci M,Sironi S,De Cobelli F,et al.Plain and gadolinium DYPA-enhanced MR imaging of hepatocellular carcinoma treated with transarterial chemoembolization[J].Abdominial Imaging,1996,21(6):488-494.
[30]肖运平.肝细胞癌介入术后疗效的影像学评价[J].中国医学影像技术,2006,22(9):1438-1441.
[31]Tanaka k,Inoue S,Numata K,et al.Color Doppler sonography of hepatocellular carcinoma before and after treatment by transcatheter arterial embolization[J].AJR Am J Roentgenol.1992,158(3):541-546.
[32]贺声,曹铁生,段云友.肝癌血管超声观测的临床病理学意义[J].国外医学肿瘤学分册,1999.26(4):237-239.
[33]Vaupl P.Kallinowski F.Okunieff P.Blood flow,oxygen and nutrient supply and metabolic microenvironment of human tumors:a review[J].Cancer Res,1989,49(23):6449-6465.
[34]Tanaka k,Inoue S,Numata K,et al.Color Doppler sonography of hepatocellular carcinoma before and after treatment by transcatheter arterial embolization[J].Am J Roentgenol,1992,158(3):541-546.
[35]韩增辉,钱蕴秋,王全华.能量多普勒:一种新的多普勒显像技术[J].中国超声医学杂志,1996,12(4):58-60.
[36]Sumi S,Yamashita Y,Mitsuzaki K,et al.Power Doppler sonography assessment of tumor recurrence after chemoembolization therapy for hepatocellular carcinoma[J].AIR,1999,172(1):67-71.
[37]Hosoki T,Mitomo M,Chor S,et al.Visualization of tumor vessels in HCC:Power Doppler compared with color Doppler and angiography[J].Acta-Radiol,1997,38(3):422-427.
[38]Fidler IJ.The biology of human cancer metastasis[J].Acta Oncologica,1991,30(6):669-675.
[39]Follkman J.Seminars in Medicine of the Beth Israel Hospital,Boston.Clinical applications of research on angiogenesis[J].N Engl J Med,1995,333(26):1757-1763.
[40]Follkman J.What is the evidence that tumors are angiogenesis dependent?[editorial].J Natl Cancer Inst,1990,82(1):4-6.
[41]Cockerill GW,Gamble JR,Vadas MA.Angiogenesis:models and modulators[J]Int Rev Cytol,1995,159:113-160.
[42]Dvorak HF,Nagy JA,Feng D.et al.Vascular permeability factor/vascular endothelial growth factor,microvascular hyperpermeability,and angiogenesis[J].Am J Pathol,1995,146(5):1029-1039.
[43]Baillie CT,Winslet MC,Bradley NJ.Tumour vasculature-a potential therapeutic target[J].Br J Cancer,1995,72(2):257-267.
[44]Park YN,Kim YB,Yang KM.et al.Increased expression of vascular endothelial growth factor and angiogenesis in the early stage multistep hepatocarcinogenesis[J].Arch Pathol Lab Med.2000.124(7):1061-1065.
[45]Potgens AJ,Westphal HR,De waal RM,et al.The role of vascular permeability factor and basic fibroblast growth factor in tumor angiogenesis[J].Biol chem.Hoppe Seyler,1995,376(2):57-70.
[46]Luiten RM,Fleuren GJ,Warnoar SO,et al.Target-specific activation of mast cells by immunoglobulin E reactive with renal cell carcinoma-associated antigen[J].Lab Invest,1996,74(2):467-475.
[47]Yamazaki,Abe S,Takekawa H,et al.Tumor angiogenesis in human lung adenocarcinoma[J].Cancer,1994,74(4):2245-2250.
[48]Martin L,Holcombe C,Renshaw C,et al.Standardising the counting technique of neovascularization in invasive breast cancer[J].Breast Cancer Res&Treat,1996,37(5):34-54.
[49]Kumar H,Heer K,Lee PW,et al.Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer[J].Clin Cancer Res,1998,4(5):1279-1285.
[50]Jubb AM,Hurwitz HI,Bai W et al.Impact of vascular endothelial growth factor-A expression,thrombospondin-2 expression,and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer[J].J Clin Oncol,2006,24(2):217-227.
[51]唐震,巫北海,韩丹.CT扫描肝细胞癌边缘肿瘤血管与肿瘤转移和预后的关系[J].实用放射学杂志,2002,18(6):464-466.
[52]Weidner N,Semple JP,Welch WR,et al.Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma[J].N Engl J Med,1991,324(1):1-8.
[53]Dales JP,Garcia S,Carpentier S,et al.Prediction of metastasis risk(11 year follow-up) using VEGF-R1,VEGF-R2,Tie-2/Tek and CD105 expression in breast cancer(n=905)[J].Br J Cancer,2004,90(6):1216-1221.
[54]Dales JP,Garcia S,Carpentier S,et al.Long-term prognostic significance of neoangiogenesis in breast carcinomas:comparison of Tie-2/Tek,CD105,and CD31 immunocytochemical expression[J].Hum Pathol,2004,35(2):176-183.
[55]徐辉,王滨,高志芹,等.肝动脉化疗栓塞对肿瘤新生血管生成的影响[J]. 实用放射学杂志,2004,20(7):620-622.
[56]廖晓锋,易继林,杨志芳,等.肝细胞癌化疗栓塞后肿瘤微血管密度的变化[J].华中科技大学学报(医学版),2002,31(5):544-546.
[57]Liao XF,Yi JL,Li XR,et al.Angiogenesis in rabbit hepatic tumor after transcatheter arterial embolization[J].World J Gastroenterol,2004,10(13):1885-1889.
[58]Weidner N,Folkman J,Pozza F,et al.Tumor angiogenesis:a new significant independent prognostic indicator in early-stage breast carcinoma[J].J Natl Cancer Inst,1992,84(24):1875-1887.
[59]Tanaka K,Inoue S,Numata K,et al.Color doppler sonography of hepatocellular carcinoma before and after treatment by transcatheter arterial embolization[J].AJR,1992,158(3):541-546.
[60]李建国.原发性肝癌的超声诊断现状与展望[J].中国医学影像技术,1998,14(14):466-467.
[61]罗葆明,文艳玲,潘景升,等.能量谐波成像声学造影在肝动脉栓塞治疗中的应用[J].中国超声医学杂志,2000,16(5):352.
[62]徐智章 主编.现代腹部超声诊断学[M].北京:科学出版社,2001:32-33.