索拉非尼防治大鼠肝癌肝移植术后肿瘤转移复发的研究

Prevention of tumor recurrence with Sorafenib after liver transplantation in rat with liver cancer

目的探讨索拉非尼防治大鼠肝癌肝移植术后肿瘤转移复发的作用。方法 Walker-256癌细胞于Wistar大鼠门静脉注射,模拟大鼠肝癌肝移植术后肿瘤转移复发模型,术后随机分为4组(每组16只):A组(对照组);B组(索拉非尼低剂量组);C组(索拉非尼中剂量组);D组(索拉非尼高剂量组),另选取E组(n=8)正常大鼠作为正常组。实验组、对照组分别于术后20d各处死8只,并同时处死正常组8只大鼠,取大鼠肝脏、肺组织,常规甲醛固定、制作石蜡切片,常规进行镜下观察;免疫组织化学方法检测肝脏、肺组织血管内皮生长因子(VEGF)及微血管密度(MVD),并对大鼠肝脏VEGF阳性率及MVD值行双变量相关性分析;对索拉非尼各剂量组及对照组剩余8只大鼠,观察其生存时间。结果索拉非尼各剂量组及对照组大鼠肝脏均出现了肿瘤转移复发,肺内均未见肿瘤转移,但索拉非尼各剂量组大鼠肝脏癌灶坏死程度较对照组轻,癌灶周边肝脏细胞受累坏死程度较对照组轻;索拉非尼各剂量组大鼠肝脏VEGF阳性率、MVD计数小于对照组(P<0.01),肝脏VEGF与MVD高度相关(rp=0.84,P<0.01);对照组、索拉非尼各剂量组大鼠肺组织VEGF、MVD差异无统计学意义(P>0.05);索拉非尼中、高剂量组大鼠生存时间长于对照组(P<0.05)。结论索拉非尼可以抑制肝癌肝移植术后大鼠肝脏内VEGF合成,降低了肝脏内癌灶MVD、抑制癌灶微血管生成,同时减轻了癌灶对正常肝细胞的损害作用,延长了肝癌肝移植术后大鼠生存时间,对防治大鼠肝癌移植术后肿瘤转移复发起到一定作用。

Objective To investigate the prevention and treatment of tumor recurrence with Sorafenib after orthotopic liver transplantation（OLT）for primary carcinoma of liver in rats.Methods Portal vein injection of Walker-256 cancer cells to establish models of metastasis and recurrence of liver after liver transplantation in rats.The rats were randomly divided into 4 groups（n=16）：Control group（group A）;Sorafenib low-dose group（group B）;Sorafenib medium-dose group（group C）;Sorafenib high-dose group（group D）;moreover,a normal group（group E,n=8）.Eight rats of each group were chosen 20 days after operation to have observation of pathological changes in liver,which were made with hematoxylin-eosin sectioning（HE）;vascular endothelial growth factor（VEGF）and microvessel density（MVD）level of liver and lung tissues were detected by immunohistochemistry;bivariate correlation analysis of VEGF and MVD of liver were used to identify the relationship between them;survival time of remaining 8 rats from control group and experimental groups of Sorafenib were observed.Results There were no differences in tumor metastasis and recurrence among control group and Sorafenib experimental groups,for it could be found metastasis and recurrence in rat liver of each group,no cancer metastasis or recurrence found in lung of each group,however,Sorafenib experimental groups had signifcantly higher ratio of cancer cell apoptosis,lower ratio of necrosis of liver cells compared with control group;VEGF-positive ratio and MVD counts of liver in each experimental group were smaller than that of control group（P0.01）;VEGF and MVD in liver were highly correlated（P0.01）,correlation coefficient rp=0.84;there was no difference of VEGF and MVD in lung tissue of each group（P0.05）;survival rate of medium-dose group and high-dose group were higher（P0.05）.Conclusions Sorafenib could inhibit synthesis of VEGF in tumor tissue,which could inhibit angiogenesis of tumor,then tumor growth,as well as invasion to normal liver cells were inhibited,and liver function damage was slighter,survival time were prolonged.As a result,there was a positive therapeutic effect of application of Sorafenib after orthotopic liver transplantation（OLT）for primary carcinoma of liver in rats.