奥沙利铂逆行隔离灌注对兔VX2移植肝癌的疗效和毒性观察

The efficacy and toxicity of Oxaliplatin in rabbit inoculated VX2 hepatic cancer during isolated hepatic perfusion with retrograde outflow

目的 对兔VX2移植肝癌行奥沙利铂（L-OHP）隔离灌注实验,观察不同流出道途径对L-OHP的抗肿瘤作用和肝脏毒性的影响.方法 将接种VX2肿瘤的新西兰兔随机分为三组,每组20只：A、B组均经肝动脉灌注5 mg/kg的L-OHP,C组为空白对照,其灌注液中不含L-OHP.A组为顺行灌注,灌注液经肝静脉流出;B、C组为逆行灌注,灌注液经门静脉流出.每组术后6 h、12 h检测血生化、肝组织病理学、血管内皮生长因子（VEGF）表达情况和肝细胞凋亡指数（AI）;A、B组行反相高效液相色谱分析法测定L-OHP浓度.结果 三组血清ALT、AST在术后6 h、12 h均显著升高,A组明显高于B和C组,各组间比较差异均有统计学意义（tALT=2.328、tALT=7.116、tALT=3.124 P＜0.05;tAST=2.547、tAST=4.710、tAST=2.238 P＜0.05）.A组术中L-OHP外周血浓度和肝组织浓度均明显高于B组（t=3.091,P＜0.05;t=2.778,P＜0.05）,但A、B组肿瘤组织及流出道L-OHP浓度比较差异无统计学意义（t=1.461,P＞0.05;t=0.223,P＞0.05）.术后12 h A组肝脏病理改变较B组严重.术后12 h A和B组VEGF表达水平较C组显著降低（tAC=2.728,P＜0.05;tBC=3.397,P＜0.01）,但A组和B组比较,差异无统计学意义（t=0.591,P＞0.05）.术后12 h A组肝细胞凋亡指数（AI）明显高于B和C组,且各组间比较差异均有统计学意义（tAB=3.689,P＜0.01;tAC=5.067,P＜0.01;tBC=2.607,P＜0.05）.结论 L-OHP隔离灌注具有明显抗肿瘤作用;化疗灌注液经门静脉逆行流出是一种较安全的区域化疗方法.

Objective To study the anti-tumor effect and liver toxicity of Oxaliplatin （L-OHP）from different outflow tracts, we implemented isolated perfusion on rabbit VX2 tumor model with L-OHP.Methods In this study, 60 rabbits in which VX2 liver cancer were established were randomly divided into three groups （ A = B = C = 20）. Group A and B were taken isolated hepatic perfusion with 5 mg/kg L-OHP,while group C was normal control, which was taken isolated hepatic perfusion without L-OHP. Perfusion fluid flowed through the hepatic veins in group A, while in group B and C perfusion fluid flowed through the portal vein. Blood biochemistry、liver histopathology 、vascular endothelial growth factor （VEGF） expression and hepatocyte apoptosis index （AI） in the postoperative 6th and 12th hour were examined. L-OHP concentration was measured during the perfusion with RP-HPLC in group A and B. Results Serum ALT、AST rose significantly in all three groups in the 6th and 12th hour postoperatively, and that in group A was higher than either group B or C. Differences in serum ALT、AST level between group A and B, B and C, A and C were all statistically significant （tALT = 2. 328、tALT =7. 116、tALT =3. 124,P 〈 0.05;tAST =2.547、tAST =4. 710、tAST = 2. 238, P 〈 0. 05 ）. The differences of L-OHP concentration in the liver and systemic circulation between group A and B was statistically significant（t =3.091, P 〈0. 05;t =2. 778,P 〈0. 05）,however the difference between group A and B of L-OHP concentration in the tumor tissue and outflow tract was not statistically significant（ t = 1. 461, P 〉 0. 05; t = 0. 223, P 〉 0. 05 ）. Hepatic pathology in group A was more serious than that in group B in the 12th hour postoperatively. The levels of VEGF expression in liver tumor tissue in postoperative 12th hour, in group A and B were significantly lower comparing with group C （tAC =2.728, P 〈 0.05;tBC =3.397,P 〈0.01）. Between group A and B, the difference was not statistically significant （ t = 0. 591, P 〉 0. 05 ）. Differences in hepatocyte apoptosis index （ AI ） in the postoperative 12th hour between group A and C, A and B, B and C were all statistically significant（ tAB=3. 689, P 〈 0. 01 ;tAC = 5. 067, P 〈 0. 01 ;tBC = 2. 607, P 〈 0. 05 ）, and with that in group A being higher than either in group B or C. Conclusions L-OHP had a significant anti-tumor effect in isolated hepatic perfusion; Chemotherapy infusion fluid flowing through the portal vein retrogradely was a more complete and safer way of regional chemotherapy than antegrade flowing through the hepatic vein.