苦参素与顺铂合用对人肝癌裸鼠皮下移植瘤组织VEGF、CD31表达的影响和意义
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摘要
目的分析苦参素与顺铂合用对人肝癌裸鼠皮下移植瘤组织血管内皮生长因子(vascular endothelial growth factor,VEGF)、血小板-内皮细胞黏附分子(CD31)表达的影响及临床意义。方法建立40只人肝癌裸鼠模型,随机分为4组(对照组、苦参素组、顺铂组、联合组),采用腹腔注射方式给药,给予对照组裸鼠注射生理盐水,给予苦参素组裸鼠注射苦参素,给予顺铂组大鼠注射顺铂,给予联合组裸鼠注射苦参素和顺铂,给药结束后第15天将4组裸鼠处死,取皮下移植瘤组织,对比4组抑瘤率,采用免疫组织化学染色法检测4组裸鼠皮下移植瘤组织中VEGF、CD31的表达情况。结果联合组裸鼠的肿瘤体积小于其他3组裸鼠,差异具有统计学意义(P<0.05)。VEGF阳性率检出率为20.00%,低于苦参素组的80.00%、顺铂组的70.00%、对照组的100.00%,差异具有统计学意义(P<0.05)。联合组裸鼠的CD31阳性率检出率为30.00%,低于苦参素组的90.00%、顺铂组的70.00%、对照组的100.00%,差异具有统计学意义(P<0.05)。结论苦参素与顺铂合用能够抑制人肝癌皮下移植瘤组织中VEGF、CD31的表达,延缓肿瘤生长。
Objective To study the effect of oxymatrine combined with cisplatin on the expression of vascular endothelial growth factor( VEGF) and platelet-endothelial cell adhesion molecule CD31 in human hepatocellular carcinoma xenografts in nude mice. Methods Nude mice bearing human hepatocellular carcinoma xenografts were randomly divided into 4 groups for intraperitoneal injections with normal saline( control),cisplatin,oxymatrine,or both oxymatrine and cisplatin. Fifteen days after the injections,the mice were sacrificed for examination of the expression of VEGF and CD31 in the subcutaneous xenografts with immunohistochemical staining. Results In the tumor-bearing mice treated with both oxymatrine and cisplatin,the tumor volume was significantly smaller than that in the other 3 groups( P < 0. 05),and the positive rate for VEGF in the subcutaneous xenograft was 20%,significantly lower than the rate of 80% in oxymatrine group,70% in the cisplatin group and 100% in the control group( P<0.05). The positive rate of CD31 in the xenograft was 30% in the combined treatment group,also significantly lower than the rates in matrine group( 90%),cisplatin group( 70%) and control group( 100%)( P < 0. 05). Conclusion Oxymatrine combined with cisplatin can inhibit the expression of VEGF and CD31 in subcutaneous xenografts of human hepatocellular carcinoma and delay tumor growth in nude mice.
Objective To study the effect of oxymatrine combined with cisplatin on the expression of vascular endothelial growth factor( VEGF) and platelet-endothelial cell adhesion molecule CD31 in human hepatocellular carcinoma xenografts in nude mice. Methods Nude mice bearing human hepatocellular carcinoma xenografts were randomly divided into 4 groups for intraperitoneal injections with normal saline( control),cisplatin,oxymatrine,or both oxymatrine and cisplatin. Fifteen days after the injections,the mice were sacrificed for examination of the expression of VEGF and CD31 in the subcutaneous xenografts with immunohistochemical staining. Results In the tumor-bearing mice treated with both oxymatrine and cisplatin,the tumor volume was significantly smaller than that in the other 3 groups( P < 0. 05),and the positive rate for VEGF in the subcutaneous xenograft was 20%,significantly lower than the rate of 80% in oxymatrine group,70% in the cisplatin group and 100% in the control group( P<0.05). The positive rate of CD31 in the xenograft was 30% in the combined treatment group,also significantly lower than the rates in matrine group( 90%),cisplatin group( 70%) and control group( 100%)( P < 0. 05). Conclusion Oxymatrine combined with cisplatin can inhibit the expression of VEGF and CD31 in subcutaneous xenografts of human hepatocellular carcinoma and delay tumor growth in nude mice.
引文
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[10]耿良,范敬,高启龙,等.人参皂苷Rg3和PEG-PLGARg3纳米微粒对Lewis肺癌小鼠的作用及其机制[J].北京大学学报(医学版),2016,48(3):496-501.DOI:10.3969/j.issn.1671-167X.2016.03.021.GENG L,FAN J,GAO Q L,et al.Preliminary study for the roles and mechanisms of 20(R)-ginsenoside Rg3 and PEGPLGA-Rg3 nanoparticles in the Lewis lung cancer mice[J].J Peking Univy(Health Sci),2016,48(3):496-501.DOI:10.3969/j.issn.1671-167X.2016.03.021.
[11]胡哲,王培恩,瞿海江.TACE联合索拉菲尼治疗晚期肝癌患者的疗效及对血清VEGF、CTGF、HIF-1α及OPN水平的影响[J].中国生化药物杂志,2017,38(4):345-347,350.DOI:10.3969/j.issn.1005-1678.2017.04.114.HU Z,WANG P E,QU H J.The dynamic changes of serum VEGF,CTGF,HIF-1 and OPN levels in patients with advanced liver cancer treated with Sola Feeney combined with TACE[J].Chin J Biochem Pharm,2017,38(4):345-347,350.DOI:10.3969/j.issn.1005-1678.2017.04.114.
[12]王启船,王青,万里新,等.食管鳞癌中T淋巴瘤侵袭转移诱导基因1、血管内皮生长因子和CD31的表达及其相关性研究[J].中国医药导报,2012,9(23):95-96.DOI:10.3969/j.issn.1673-7210.2012.23.040.WANG Q C,WANG Q,WAN L X,et al.The study of expression of Tiam1,VEGF and CD31 in esophageal squamous cell carcinoma and their correlations of them[J].Chin Med Herald,2012,9(23):95-96.DOI:10.3969/j.issn.1673-7210.2012.23.040.
[13]王刚,程雪,张祥林,等.shRNA-CXCR7联合TRAIL对人肝癌SMMC-7721细胞裸鼠皮下移植瘤生长的影响[J].中国生化药物杂志,2016,37(1):28-31.WANG G,CHENG X,ZHANG X L,et al.Effect of shRNA-CXCR7 combined with TRAIL on subcutaneous transplantation tumor of SMMC-7721 cell line in nude mice[J].Chin J Biochem Pharm,2016,37(1):28-31.
[14]高军,祝小英,石庆芳,等.沙利度胺联合表阿霉素对小鼠H22肝癌移植瘤的生长抑制研究[J].中国临床药理学杂志,2016,32(2):170-173.DOI:10.13699/j.cnki.1001-6821.2016.02.024.GAO J,ZHU X Y,SHI Q F,et al.Mechanism and inhibition of thalidomide combined with epirubicine on the growth of transplanted H22 hepatocellular carcinoma in mice[J].Chin J Clin Pharmacol,2016,32(2):170-173.DOI:10.13699/j.cnki.1001-6821.2016.02.024.
[15]方蕾,赵展,吴乾能,等.恩度联合TACE术治疗肝癌对患者血清VEGF、HIF-1A、OPN、MMP-9的影响及意义[J].中华全科医学,2016,14(3):412-414.DOI:10.16766/j.cnki.issn.1674-4152.2016.03.025.FANG L,ZHAO Z,WU Q N,et al.Influence and significance of hepatic transcatheter arterial chemoembolization combime with endostar on levels of serum VEGF,HIF-1A,OPN and MMP-9 in patients with hepatocellular carcinoma[J].Chin J Gen Pract,2016,14(3):412-414.DOI:10.16766/j.cnki.issn.1674-4152.2016.03.025.
[2]周佳美,向慧玲,朱争艳,等.大鼠CBRH-7919肝癌细胞诱导大鼠骨髓间充质干细胞向血管内皮细胞分化的初步研究[J].中国现代医学杂志,2012,22(29):21-25.ZHOU J M,XIANG H L,ZHU Z Y,et al.Differentiation of bone marrow mesenchymal stem cells into endothelial cells induced by rat CBRH-7919 hepatoma cells in vitro[J].Chin J Mod Med,2012,22(29):21-25.
[3]Cristina C,Perez-Millan MI,Luque G,et al.VEGF and CD31association in pituitary adenomas[J].Endocr Pathol,2010,21(3):154-160.DOI:10.1007/s12022-010-9119-6.
[4]徐昊平,郭睿,金冶宁,等.肺腺癌靶向基因放射治疗的体内研究及小动物正电子发射计算机体层摄影评价疗效的可行性[J].中华肿瘤杂志,2014,36(5):329-334.DOI:10.3760/cma.j.issn.0253-3766.2014.05.003.XU H P,GUO R,JIN Y Y,et al.Gene-targeted radiation therapy mediated by radiation-sensitive promoter in lung adenocarcinoma and the feasibility of micro-PET/CT in evaluation of therapeutic effectiveness in small animals[J].Chin J Oncol,2014,36(5):329-334.DOI:10.3760/cma.j.issn.0253-3766.2014.05.003.
[5]刘翠云,董惠,成慧,等.探讨nm23-H1、VEGF-C和CD31在甲状腺乳头状癌中表达的相关性[J].诊断病理学杂志,2017,24(4):284-287.DOI:10.3969/j.issn.1007-8096.2017.04.013.LIU C Y,DONG H,CHENG H,et al.Correlation between VEGF-C,nm23-H1 and CD31 in papillary thyroid carcinoma[J].Chin J Diagn Pathol,2017,24(4):284-287.DOI:10.3969/j.issn.1007-8096.2017.04.013.
[6]李明琰,何文凯,陈建威,等.Ad-HIF-1α-Trip肌肉注射对大鼠缺血肢体血管新生和血液灌注的影响[J].第三军医大学学报,2012,34(15):1518-1522.LI M Y,HE W K,CHEN J W,et al.Effects of Ad-HIF-1α-Trip transfer on angiogenesis and blood perfusion in a rat model of hind limb ischemia[J].J Third Mil Med Univ,2012,34(15):1518-1522.
[7]Kasprzak A,Surdacka A,Tomczak M,et al.Expression of angiogenesis-stimulating factors(VEGF,CD31,CD105)and angiogenetic index in gingivae of patients with chronic periodontitis[J].Folia Histochem Cytobiol,2012,50(4):554-564.DOI:10.5603/20324.
[8]符黄德,罗起胜,邓元央,等.肝癌衍生生长因子和血管内皮生长因子在脑胶质瘤中的表达及其与肿瘤微血管密度的相关性研究[J].中国全科医学,2016,19(17):2019-2023.DOI:10.3969/j.issn.1007-9572.2016.17.008.FU H D,LUO Q S,DENG Y Y,et al.Expression of Hepatoma-derived Growth Factor and Vascular Endothelial Growth Factor and Their Correlation With Tumor Microvessel Density in Gliomas[J].Chin Gen Pract,2016,19(17):2019-2023.DOI:10.3969/j.issn.1007-9572.2016.17.008.
[9]司春枫,鲁美钰,王巧云,等.VEGF融合蛋白疫苗联合环磷酰胺抗小鼠H22肝癌实验研究[J].中国药理学通报,2017,33(5):617-621.DOI:10.3969/j.issn.1001-1978.2017.05.006.SI C F,LU M Y,WANG Q Y,et al.Improved antitumor efficacy by combinationtreatment with recombined VEGF protein vaccineand cyclophosphamide in H22 hepatocellular carcinoma bearing-mice[J].Chin Pharmacul Bull,2017,33(5):617-621.DOI:10.3969/j.issn.1001-1978.2017.05.006.
[10]耿良,范敬,高启龙,等.人参皂苷Rg3和PEG-PLGARg3纳米微粒对Lewis肺癌小鼠的作用及其机制[J].北京大学学报(医学版),2016,48(3):496-501.DOI:10.3969/j.issn.1671-167X.2016.03.021.GENG L,FAN J,GAO Q L,et al.Preliminary study for the roles and mechanisms of 20(R)-ginsenoside Rg3 and PEGPLGA-Rg3 nanoparticles in the Lewis lung cancer mice[J].J Peking Univy(Health Sci),2016,48(3):496-501.DOI:10.3969/j.issn.1671-167X.2016.03.021.
[11]胡哲,王培恩,瞿海江.TACE联合索拉菲尼治疗晚期肝癌患者的疗效及对血清VEGF、CTGF、HIF-1α及OPN水平的影响[J].中国生化药物杂志,2017,38(4):345-347,350.DOI:10.3969/j.issn.1005-1678.2017.04.114.HU Z,WANG P E,QU H J.The dynamic changes of serum VEGF,CTGF,HIF-1 and OPN levels in patients with advanced liver cancer treated with Sola Feeney combined with TACE[J].Chin J Biochem Pharm,2017,38(4):345-347,350.DOI:10.3969/j.issn.1005-1678.2017.04.114.
[12]王启船,王青,万里新,等.食管鳞癌中T淋巴瘤侵袭转移诱导基因1、血管内皮生长因子和CD31的表达及其相关性研究[J].中国医药导报,2012,9(23):95-96.DOI:10.3969/j.issn.1673-7210.2012.23.040.WANG Q C,WANG Q,WAN L X,et al.The study of expression of Tiam1,VEGF and CD31 in esophageal squamous cell carcinoma and their correlations of them[J].Chin Med Herald,2012,9(23):95-96.DOI:10.3969/j.issn.1673-7210.2012.23.040.
[13]王刚,程雪,张祥林,等.shRNA-CXCR7联合TRAIL对人肝癌SMMC-7721细胞裸鼠皮下移植瘤生长的影响[J].中国生化药物杂志,2016,37(1):28-31.WANG G,CHENG X,ZHANG X L,et al.Effect of shRNA-CXCR7 combined with TRAIL on subcutaneous transplantation tumor of SMMC-7721 cell line in nude mice[J].Chin J Biochem Pharm,2016,37(1):28-31.
[14]高军,祝小英,石庆芳,等.沙利度胺联合表阿霉素对小鼠H22肝癌移植瘤的生长抑制研究[J].中国临床药理学杂志,2016,32(2):170-173.DOI:10.13699/j.cnki.1001-6821.2016.02.024.GAO J,ZHU X Y,SHI Q F,et al.Mechanism and inhibition of thalidomide combined with epirubicine on the growth of transplanted H22 hepatocellular carcinoma in mice[J].Chin J Clin Pharmacol,2016,32(2):170-173.DOI:10.13699/j.cnki.1001-6821.2016.02.024.
[15]方蕾,赵展,吴乾能,等.恩度联合TACE术治疗肝癌对患者血清VEGF、HIF-1A、OPN、MMP-9的影响及意义[J].中华全科医学,2016,14(3):412-414.DOI:10.16766/j.cnki.issn.1674-4152.2016.03.025.FANG L,ZHAO Z,WU Q N,et al.Influence and significance of hepatic transcatheter arterial chemoembolization combime with endostar on levels of serum VEGF,HIF-1A,OPN and MMP-9 in patients with hepatocellular carcinoma[J].Chin J Gen Pract,2016,14(3):412-414.DOI:10.16766/j.cnki.issn.1674-4152.2016.03.025.