姜黄素联合肝动脉栓塞对兔VX-2肝移植瘤的生长及VEGF表达的影响
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
目的:碘化油栓塞肿瘤血管能引起残余肿瘤细胞内血管内皮生长因子VEGF蛋白的表达增强;本实验采用姜黄素联合栓塞方法,实验观察姜黄素联合肝动脉栓塞兔VX-2肝移植瘤对肿瘤的生长及VEGF蛋白的影响;探讨姜黄素能否抑制肿瘤的生长并能否抑制碘化油栓塞引起的残余肿瘤细胞内VEGF蛋白的表达增强。
     方法:40只新西兰大白兔接种VX-2瘤块复制肝癌模型,经肝动脉灌注栓塞后有36只达到要求合格,将这36只实验兔随机分成4组。A组:肝素水组(模型组);B组:姜黄素灌注组;C组:碘化油栓塞组;D组:姜黄素碘化油乳剂栓塞组。治疗前和治疗后2周分别用MRI测量肿瘤直径,计算肿瘤体积和体积变化,治疗后2周处死实验兔,取出标本,采用免疫组化和Western印迹测定残余肿瘤中VEGF蛋白的表达。
     结果:
     1、肿瘤体积(cm3)变化:A组18.30±0.61;B组:18.36±1.11;C组:6.06±1.13;D组:5.97±0.92。两两之间比较:B组与A组比较:差异无显著性,P值:0.88(P>0.05);C组与A组比较:差异有显著性,P值<0.01(P<0.05);D组与A组比较,差异有显著性,P值<0.010(P<0.05);C组与B组比较:差异有显著性,P值<0.01(P<0.05);D组与B组比较:差异有显著性,P值<0.01(P<0.05);D组与C组比较:差异无显著性,P值0.831(P>0.05)。
     2、免疫组化VEGF蛋白的平均光密度值:A组:0.599±0.182;B组:0.545±0.284;C组:0.867±0.210;D组:0.603±0.186。两两之间比较:B组与A组比较,P值为0.46(P>0.05),差异无显著性;C组与A组比较,P值<0.01(P<0.05),差异有显著性;D组与A组比较,P值0.952(P>0.05),差异无显著性;C组与B组比较,P值<0.01(P<0.05),差异有显著性;D组与B组比较,P值0.424(P>0.05),差异无显著性;D组与C组比较,P值0.01(P<0.05),差异有显著性。
     3、Western印迹杂交测定VEGF蛋白表达水平:对照组(A组):46.17±13.44;B组:47.57±15.02;C组:82.56±18.85;D组:53.84±16.55。两两之间比较:B组与A组比较,P值为0.795(P>0.05),差异无显著性;C组与A组比较,P值<0.01(P<0.05),差异有显著性;D组与A组比较,P值0.157(P>0.05),差异无显著性;C组与B组比较,P值<0.01(P<0.05),差异有显著性;D组与B组比较,P值0.242(P>0.05),差异无显著性;D组与C组比较,P值<0.01(P<0.05),差异有显著性。
     结论:
     1、单用姜黄素不能抑制肿瘤的生长,也不能有效抑制残余肿瘤细胞内VEGF蛋白的表达。
     2、姜黄素联合栓塞兔VX-2肝移植瘤能够有效抑制碘化油栓塞引起残余肿瘤细胞内VEGF蛋白的表达增高,但未见明显其抑瘤效应。
Objective:
     The way of tumor vessels embolismed by iodinate oil can enhance the express of vascular endothelial growth factor (VEGF) protein in residual tumor cell;the experient associated curcumin with embolizer in order to observe the effect on the expression of tumor growth and VEGF in rabbit VX-2 liver tumor transcatheter arterial embolization(TAE) combining curcumin; probing the curcumin was or was not able to inhabit the growth of tumor and the enhancement of VEGFprotein in residual tumor brought out by iodinate oil。
     Methods:
     VX-2 carcinoma pieces were surgically implanted into the left liver lopes of 40 New Zealand white rabbitsin order to build the model of liver cancer,those of thirty-six were successfully transcathetered arterial embolization.those were randomly divided into the four groups,with nine rabbits in each group. Controlgroup:treated with heparin saline; B group:treated with hepatic arterial infusion therapy combining curcumin;C group:Hepatic artery embolism combining iodized oil; D group:treated with transcatheter arterial emboli-zation combining curcumin and iodized oil. Two weeks after embolism, the rabbits were sacrificed and the tumors were taken out. The volume of tumor and the rate of tumor grate was calculated before and after TAE. Immunohistochemistry and Western blotting were used to detect expression of vascular endothelial growth factor (VEGF) protein。
     Results:
     1. Variation of tumor volume A group:18.30±0.61; B group:18.36±1.11; C group:6.06±1.13;D group:5.96±0.92.draw a parallel between the two:the volume of B group was not supressed and comparedwith the volume of A group,it had not obvious differences(P=0.88);the volume of C group was supressed and comparedwith the volume of A group, it had obvious differences(P<0.01); the volume of D group was not supressed and comparedwith the volume of A group, it had obvious differences(P=0.175); the volume of C group was supressed and comparedwith the volume of B group, it had obvious differences(P<0.01); the volume of D group was supressed and comparedwith the volume of B group, it had obvious differences (P<0.01); the volume of D group was not supressed and comparedwith the volume of C group, it had not obvious differences(P=0.831).
     2.VEGF protein was detected by Immunohistochemistry as follow:A group 0.599±0.182, B group:0.545±0.284, C group:0.867±0.210, D group:0.603±0.186; draw a parallel between the two:the volume of B group was not supressed and comparedwith the volume of A group,it had not obvious differences(P=0.46);the volume of C group was supressed and comparedwith the volume of A group, it had obvious differences(P<0.01); the volume of D group was not supressed and comparedwith the volume of A group, it had obvious differences(P=0.592); the volume of C group was supressed and comparedwith the volume of B group, it had obvious differences(P<0.01); the volume of D group was supressed and comparedwith the volume of B group, it had obvious differences(P:0.242); the volume of D group was not supressed and comparedwith the volume of C group, it had not obvious differences(P=0.01).The trend of VEGF protein expression was as the same as that of VEGF he relative light intensity
     Conclusions:
     1.Sing-use curcumin neither inhibit effectively the grate of tumor,nordepress the expression of VEGF protein inresidual tumor cell.
     2.curcumin epress the enhancement expression of VEGF protein inresidual tumor cell brought out by iodinate oil.,but curcumin can not obviously inhibit the grate of tumor.
引文
[1]Stewart BW,Kleihues P.World Cancer Report [M].Lyon IARC,2003,1-351.
    [2]陈建国,宋新明.中国肝癌发病水平的估算及分析.[J]中国肿瘤,2005,14(1):28-31.
    [3]陈爱民,徐耀初,沈靖等.原发性肝癌危险因素的病例-对照研究.[J].现代预防医学,2001,3(28):299-301.
    [4]Nakamura K,Zen Y,Sato Y,et al.Vascular endothelial growth factor,its recept OR flk-1,and hypoxia inducible factor-1alpha are involved i malignant transformation in dysplastic nodules of the liver.[J].Hum Pathol.2007,38(10):1532-1546.
    [5]王洪海,任宁,张辉等,联合检测VEGF、PD-ECGF和PNCA表达预测肝细胞癌术后复发及预后.[J].中国临床医学,2005,12(3):448-451.
    [6]卞修武,对肿瘤血管生成研究之肿瘤微血管构筑表型异质性的思考.[J].中华病理学杂志,2006,35(3):129-131.
    [7]Passe TJ,Bluemke DA,Siegelman SS.Tumor angiogenesis:tutorial on implications for imaging.[J].Radiology,1997,203(3):593-600.
    [8]顾宇,陆枫林VEGF促进肝癌SMMC-7721细胞侵袭性的自分泌机制.[J]世界华人消化杂志,2009;17(32):3292-3295.
    [9]宁厚法,王滨,曹贵文等,经导管肝动脉栓塞化疗术(TACE)对肝癌细胞凋亡相关蛋白fas,bax和bcl-x1表达影响的相关研究.[J].实用放射学杂志,2004,20(3):248-250.
    [10]Tseng PL,Tai MH,Huang CC,et al.Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients.[J].Journal of Surgical Oncology,2008,98(5):349-357.
    [11]Hirohashi K,Yamamoto T,Uenishi T,et al.CD44 and VEGF expression in extrahepatic metastasis of human hepatocellular carcinoma.[J]. Hepatogastroenterology,2004,51 (58): 1121-1123.
    [12]Cui J, Dong BW, Liang P, et al. The influence of c-Myc, Ki-67, MMP-2 and VEGF expression on the prognosis of hepato-cellular carcinoma patients with tumor resection[J]. ChungHua Kan Tsang Ping Tsa Chih,2004,12(11):660-2
    [13]Ganeshan A,Upponi S,Hon LQ,et al.Hepatic arterial infusion of chemotherapy:the role of diagnostic and interventional radiology. [J].Ann Oncol,2008,19(5):847-851.
    [14]Iguchi T,Arai Y,Inaba Y,Yamaura H,Sato Y,Miyazaki M,Shimamoto H.Hepatic arterial infusion chemotherapy through a port-catheter system as preoperative initial therapy in patients with advanced liver dysfunction due to synchronous and unresectable liver metastases from colorectal cancer.Cardiovasc Intervent Radiol2008;31:86-90
    [15]Takayasu K,Anii S,Ikai I,et al.Prospective Cohort Study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 Patients.[J].Gastroenterology,2006,131(2): 461-469.
    [16]Mathonnet M,Descottes B,Valleix D,et al.Quantitative Analysis Using ELISA of Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor in Human Colorectal Cancer, Liver Metastasis of Colorectal Cancer and Hepatocellular Carcinoma.[J].World J Gastroenteml,2006,12(23):3782-3783.
    [17]Park YN,Kim YB,Yang KM,et al.Increased Expression of Vascular Endothelial Growth Factor and Angiogenesis in the Early Stage of Multistep Hepatocarcinogenesis.[J].Arch Pathol Lab Med,2000,124(7):1061-1065.
    [18]Song BC,Chung YH,Kim JA,et al.Association between Insulin-like Growth Factor-2 and Metastases after Transcatheter Arterial Chemoembolization in Patients with Hepatocellular Carcinoma:a prospective study.[J].Cancer,2001,91(12):2386-2393.
    [19]Maataoui A,Qian J,Vossoughi D,et al.Transarterial Chemoembolization alone and in Combination with other Therapies:A Comparative Study in an Animal HCC Model.[J].Eur Radiol,2005,15(1):127-133.
    [20]Yoon CJ,Chung JW,Park JH,et al.Transcatheter arterial embolization with 188 Rhenium-HDD-labeled iodized oil in rabbit VX2 liver tumor.[J].J Vasc Interv Radiol,2004, 15(10):1121-1128.
    [21]]Hong K,Kobeiter H,Georgiades CS,et al.Effects of the type of embolization particles on carboplatin concentration in liver tumors after transcatheter arterial chemoembolization in a rabbit model of liver cancer. [J].J Vasc Interv Radiol,2005,16(12):1711-1717.
    [22]YaRu Y,XiaoYun X, et al.Establishment of rabbit model bearing VX2 liver tumor and ultrasound evaluation.[J].Chin J Med Imaging Technol,2003,19(12):1603-1605.
    [23]DongFeng H, Ke X, et al.The establishment of retrofit model of VX2 carcinoma in rabbit liver and spiral CT evaluation.[J].Chin J Med Imaging Technol,2005,21(12):1873-1876.
    [24]Guang-qi L,Yu-xiu C et al. Establishment of a modified model of Vx-2 carcinoma in rabbit liver.[J].Acta Academiae Medicinae CPAPF,2007,16 (4):369-372.
    [25]Hanahan D, Folkman J.Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.[J].Cell,1996,86(5):353-364.
    [26]Cheng Kai Z, HuiMing L, Li X,et al. Establishment of rabbit model bearing liver VX2 tumor experimentation and discussion of the selective hepatic arterial catheterization.[J]. JlnterventRadiol,2006,15(2):101-104.
    [27]Dzodic R, Gomez-Abuin G, Rougier P,et al.Pharmacokinetic advantage of intra-arterial hepatic oxaliplatin administration:comparative results with cisplatin using a rabbit VX2 tumor model.[J].Anticancer Drugs,2004,15(6):647-650.
    [28]Tunstall RG,Sharma RA,Perkins S,et al.Cyclooxygenase-2 expression and oxidative DNA adducts in murine intestinal adenomas:Modification by dietary curcumin and implications for clinical trials.[J].European Journal of Cancer,2006,42:415-421.
    [29]Lev-Ari S,Zinger H,Kazanov D,et al.Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells. [J].Rheumatology (Oxford),2006,45(2):171-177.
    [30]孙军,王贺玲等,姜黄素对人肝癌细胞中血管内皮生长因子表达的影响.[J].中华消化杂志,2006,26:(12):843-844.
    [31]黄冬生,张磊等.姜黄素对小鼠S180肉瘤肿瘤血管形成抑制作用研究.[J].现代医院.2009.9(5):15-16.
    [32]Christopher R.Ireson,DonaldJ.L.Jones,et,al,Metabolism of the Cancer Chemopreventive Agent Curcuminin and RatIntestine.Cancer Epidemiology,Biomarkers &Prevention,2002 Jan(11):105-111.
    [33]Sarah Perkins,Riehard D,Verschoyle,Kirsti Hill,etal, Chenmopreventive efficacy and pharmacokinetics of curcumin in the Min/+mouse,a model of familial adenomatous polyposis.Cancer Epidemiology,Biomarkers&preventions,2002(11):535-540.
    [34]harma R A, Steward W P, Gescher A J-Pharmacokinetics and pharmacodynamics of curcumin [J]-AdvExp Med Biol,2007,595:453-470.
    [35]Anand P, Kunnumakkara A B, Newman R A,et al-Bio-availability of curcumin:problems and promises [J].Mol Pharm,2007,4(6):807-818-
    [1]Folkman J.What is the evidence that tumors are angiogenesis dependent?[J].J Natl Cancer Inst,1990,82,4-6.
    [2]ina murine fibrosarcoma suppresses primary tumor growth and produce long-term dormancy of metastasis[J].J Clin Invest,1998,101,1055-1061.
    [3]Ferrara N, Henzel WJ. Pituitary follicular cells secrete a no-vel heparin-binding growth factor specific for vascular endo-thelial cells [J]. Biochem Biophys Res Commun,1989; 161(2):851-858.
    [4]Teramoto S, Arihiro K, Koseki M,et al. Role of vascular endothelial growth factor-C and-D mRNA in breast cancer [J]. Hiroshima J Med Sci,2008; 57(2):73-88.
    [5]Thelen A, Scholz A, Benckert C,et al. VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hep-atocellular carcinoma [J]. Int J Cancer,2008; 122 (11):2471-2481.
    [6]Brekken RA, Overholser JP, Stastny VA,etal. Selective in-hibition of vascular endothelial growth factor (VEGF) recep-tor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF anti-body blocks tumor growth in mice [J]. Cancer Res,2000; 60(18):5117-5124.
    [7]Brodsky SV, Mendelev N, Melamed M,etal. Vascular den-sity and VEGF expression in hepatic lesions [J]. J Gastroint-estin Liver Dis,2007; 16(4):373-377.
    [8]Li Q, Xu B, Fu L,etal. Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma [J]. JExp Clin Cancer Res,2006; 25(3):403-409.
    [9]顾宁,陆枫林.VEGF促进肝癌SMMC-7721细胞侵袭性的自分泌机制.世界华消化杂志2009;17:3292-3295.
    [10]宁厚法,王滨,曹贵文,等.经导管肝动脉化疗栓塞术(TACE)对肝细胞癌凋亡相关蛋白fas,bax和bcl-xl表达影响的相关研究[J].实用放射学杂志,2004,20(3):248-250.
    [11]Ganeshan A,Upponi S,Hon LQ,Warakaulle D,Uberoi R.Hepatic arterial infusion of chemotherapy:the role of diagnostic and interventional radiology.Ann Oncol 2008; 19: 847-851。
    [12]guchi T,Arai Y,Inaba Y,Yamaura H,Sato Y,Miyazaki M,Shimamoto H.Hepatic arterialinfusion chemotherapy through a port-catheter system as preoperative initial therapy in patients with advanced liver dysfunction due to synchronous and unresectable liver metastases from colorectal cancer.Cardiovasc Intervent Radiol 2008;31:86-90.
    [13]Chan AO,Yuen MF,Hui CK,et al.A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoemboliza-tion in patients with hepatocellular carcinoma.Cancer,2002,94(6):1747-1752
    [14]Lo CM,Ngan H,Tso WK,et al.Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.Hepatology,2002,35(5): 1164-1171
    [15]von-Marschall Z,Cramer T,Hocker M,et al.Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma.Gut,2001,48(1):87-96
    [16]An FQ,Matsuda M,Fujii H,et al.Expression of vascular endothelial growth factor in surgical specimens of hepatocellular carcinoma.J Cancer Res Clin Oncol,2000,126(3):153-160
    [17]TKrejsgaard, CSVetter-Kauczok, AWoetmann, et a.l Molecular target for therapy Jak 3-and JNK-dependent vascular endothelial growth factor expression in cutaneousT-cell lymphoma [J]. Leukemia,2006,20:1759-1766.
    [18]TKrejsgaard, CSVetter-Kauczok, AWoetmann, et a.l Molecular target for therapy Jak 3-and JNK-dependent vascular endothelial growth factor expression in cutaneousT-cell lymphoma [J]. Leukemia,2006,20:1759-1766.
    [19]马海清,许林锋.姜黄素抗血管生成作用及在肝癌介入治疗中的应用前景[J].国外医学:临床放射学分册,2006,29(6):412-415.0
NGLC 2004-2010.National Geological Library of China All Rights Reserved.
Add:29 Xueyuan Rd,Haidian District,Beijing,PRC. Mail Add: 8324 mailbox 100083
For exchange or info please contact us via email.