Regional intra-arterial infusion chemotherapy for pancreatic cancer of dogs with the mixture of lipid emulsion-cisplatin: an experimental study 作者： 李强 王茂强 段留新 宋鹏 敖国昆 廖洪波 宋晶莹 作者单位： 解放军总医院第二附属医院放射科,北京,100091 解放军总医院介入放射科临床药理实验室解放军总医院第二附属医院病理科,北京,100091 关键词： 胰腺肿瘤 脂肪乳剂,静脉注射用 顺铂 放射摄影术,介入性 动物实验 英文关键词： 分类号： R73 基金项目： 刊名： 《中华放射学杂志》 英文刊名： CHINESE JOURNAL OF RADIOLOGY 期刊类别： R8 出版年份/卷/刊期： 2009/ 43/ 2 栏目： 实验研究 页码： 191-195 摘要：
目的 探讨经动脉灌注脂肪乳顺铂混合液,行胰腺局部灌注化疗治疗胰腺癌的效果及作用机制.方法 24只健康杂种犬,按随机表法分为A、B、C、D组,每组6只.4组顺铂用量均为4 mg/kg.A、B组以20%脂肪乳为溶剂,配制成顺铂-脂肪乳混合液,A组用量为2 ml/kg、B组用量为1 ml/kg;C、D组以生理盐水为溶剂,配制成顺铂-生理盐水溶液,C组用量为2 ml/kg、D组为1 ml/kg.置管至实验动物脾动脉开口部,根据各组的用药标准,分别将配制好的药物经动脉灌注到胰腺肿瘤区.分别于给药后即刻及3、5、10、20、30、40、50、60 min采集外周静脉血,60 min后取胰腺、胰周和肝、肾、脾等组织,测定血液和组织匀浆内顺铂的浓度,计算实验犬血液的时间-药物浓度曲线下面积(AUC)、初始药物浓度(C0)及生物半衰期(t1/2),并观察组织病理改变.组织染色采用HE染色.4组AUC、C0、t1/2间比较,采用方差分析,组间两两比较采用q检验;A、B组组织中顺铂浓度的比较用成组t检验,数据方差不齐时采用t\"检验.结果 AUC、C0、t1/2在A组分别为(54.5±10.1)%、(2.6±0.5)mg/L、(16.7±3.6)min,B组分别为(18.3±6.0)%、(1.5±0.2)mg/L、(47.9±11.1)min,C组分别为(116.7±20.6)%、(6.5±0.4)mg/L、(10.5±2.8)min,D组分别为(126.6±30.7)%、(5.5±0.4)mg/L、(10.1±3.1)min,4组间比较差异有统计学意义(AUC、C0、t1/2的F值分别为42.42、249.61、12.48,P值均<0.01).A、B组的AUC和C0明显低于C、D组(A组与C组、B组与D组比较AUC,t值分别为6.64、8.49,比较C0的t值分别为16.34、22.30,P值均<0.01),t1/2明显长于C、D组(A组与C组、B组与D组比较,t值分别为3.36、3.71,P值均<0.01));B组的AUC、C0明显低于A组(t值分别为7.57、5.48,P值均<0.01),t1/2长于A组(t值为3.22,P<0.05).B组的胰左叶、胰腺角中顺铂含量较A组增高[B组分别为0.18、0.18 mg/L,A组分别为0.05、0.05 mg/L],差异有统计学意义(t值分别为2.52、2.73,P值均<0.05);胰腺右叶和脾脏组织中的顺铂浓度两组比较差异无统计学意义[B组分别为0.11、0.29 mg/L,A组分别为0.07、0.24 mg/L,P值均>0.05].病理检查所见:A、B组犬胰腺、胰周淋巴结、肝脏、脾脏有少量炎细胞浸润及血管扩张充血,血管内可见脂肪乳颗粒.其余组织及C、D组病理检查未见异常.结论 脂肪乳作为溶剂可使顺铂在胰腺的浓度显著增高、进入血循环的药物总量减少.进入组织的药物量与脂肪乳内所含顺铂的浓度有关,浓度越高,进入组织内的药物越多. 英文摘要： Objective To approach the mechanism and efficacy of regional intra-arterial infusion chemotherapy with the mixture of lipid emulsion-CDDP (LE-CDDP) for treatment of locally advanced pancreatic cancer. Methods Twenty-four health dogs were divided into four groups (group A, B, C, and D). The dosage of CDDP was used in 4 mg/kg/body weight for each animal The 20%LE, as a solvent, was used in the experimental animals with 2 ml/kg/ body weight (group A) and 1 ml/kg/bedy weight (group B), respectively. Normal sodium (NS) as a solvent was used as control with 2 ml/kg/bedy weight (group C) and 1 ml/kg/body weight (group D), respectively. The LE-CDDP mixture and the NS-CDDP mixture were infused into the proximal segment of splenic artery under the DSA, with transfemoral arterial approach. Blood samples were collected after infusion at 0,3,5,10,20,30,40,50,60 min and the tissues were obtained after the 60 min\"s blood sample was collected. Blood samples, absorbent gland in peripancreas, liver, spleen, kidney, heart, portal vein, the superior segment of jejunal and pancreas and parapancreatic tissues were obtained for CDDP concentration analysis and histopatholngic examination. Results The values of the area under curve (AUC), the incipient serum concentration ( C0 ) and the elimination half-life (t1/2 ) of the serum CDDP concentration-time curve in four groups were A (54. 5 ± 10.1)%,(2.6±0.5) mg/L, (16.7±3.6) min;B (18.3±6.0)%,(1.5±0.2) mg/L, (47.9 ± 11.1) min; C (116.7±20.6)%, (6.5±0.4) mg/L, (10.5±2.8) min and D (126.6±30.7)%, (5.5±0.4) mg/L, ( 10. 1±3. 1 ) min, respectively. There were significant difference among these four groups ( F(AUC) = 42. 42, F(C0) = 249. 61, F( t1/2 ) = 12. 48, P < 0. 01 ). The values of AUC and C0 in the group A were significantly lower than those in the group C (t(AUC) = 6. 64,t(C0) = 16. 34, P <0. 01 ), and the corresponding values in the group B being also significantly lower than those in the group D (t(AUC) = 8.49, t(C0) =22. 30, P<0. 01 ). The value t1/2 in the group A was significantly longer than that of in the group C ( t = 3.36, P < 0. 01 ), and that of group B was also significantly longer than that of group D ( t = 3.71, P <0. 01 ). The values of AUC and C0 in the group B were significantly lower than those in the group A (t(AUC) = 7. 57, t(C0) = 5.48, P < 0. 01 ), and the value t1/2 in the group B was significantly longer than that in the group A (t = 3.22, P < 0. 05 ). The concentrations of the left lobe and horn of pancreas were higher in the group B (0. 18, 0. 18 mg/L) than those in the group A (0. 05, 0. 05 mg/L) (t =2. 52, 2. 73, P < 0. 05). The tissue CDDP concentration of the right lobe of pancreas and spleen were no significant difference between group A ( 0. 11, 0. 29 mg/L ) and group B ( 0. 07, 0. 24 mg/L) ( P > 0. 05 ). Perivascular lymphocytic and neutrophilic infiltration, congestion and hemorrhage were found in the pancreas, parapancreatic absorbent gland, liver and spleen in the group A and group B. The micro-particles of intralipid were present in the capillary vessel of these tissues. No specific pathological changes were found in other groups and organs. Conclusions The regional intra-arterial infusion with LE-CDDP mixture could increase the pancreatic CDDP concentration, meanwhile, it also could decrease the serum CDDP concentration. The more of the CDDP concentration in the LE-CDDP mixture, the more CDDP concentration at the pancreatic tissue accordingly.