重组人血管内皮抑制素联合顺铂对小鼠腹水瘤抑制作用及其机制探讨  

Inhibition and mechanism on combination of recombinant human endostatin and cisplatin in mouse model bearing S180 tumor ascite

作　　者：魏红梅 秦叔逵[2] 殷晓进 陈亚利 华海清[2] 王琳[2] 杨宁蓉[2] 陈映霞[2] 刘秀峰[2] 

机构地区：[1]青岛市中心医院肿瘤综合治疗科,山东青岛266042 [2]中国人民解放军81医院肿瘤中心,江苏南京210002 [3]江苏先声药物有限公司研究院,江苏南京210042

出　　处：《中华肿瘤防治杂志》2015年第6期442-446,共5页Chinese Journal of Cancer Prevention and Treatment

基　　金：中国博士后科学基金(20090451574);江苏省博士后基金(820901063C)

摘　　要：目的 研究重组人血管内皮抑制素（恩度）联合顺铂治疗小鼠S180腹水瘤的有效性和安全性,并探索其相关作用机制.方法 应用小鼠S180细胞株建立腹水瘤动物模型.120只造模后的ICR小鼠随机分为对照组（0.9％ NaCl,d1～d10）、恩度组（恩度8 mg/kg,d1～d5,d7～d10;0.9％ NaCl,d6）、顺铂组（顺铂0.04 mg/kg,d6;0.9％ NaCl d1～d5,d7～d10）和恩度联合顺铂组（恩度8mg/kg,d1～d5,d7～d10;顺铂0.04 mg/kg,d6）.记录各组小鼠体质量、腹水体积、腹水中肿瘤细胞、红细胞数以及生存期;检测各组小鼠的腹膜渗透性和肝肾功能;流式细胞仪检测腹水肿瘤细胞的凋亡率;ELISA方法检测腹水中血管内皮生长因子（vascular endothelial growth factor,VEGF）和基质金属蛋白酶2（matrix metalloproteinases 2,MMP-2）的表达.结果 恩度联合顺铂组小鼠的腹水体积为（2.1±1.0） mL,肿瘤细胞数为（10.6±2.5）×107 mL-1,红细胞数为（12.0±3.1）×107 mL-1,上述各指标均低于对照组、恩度组和顺铂组.联合组的中位存活期为24.1d,明显长于对照组（12.7 d）、恩度组（16.8 d）和顺铂组（18.9 d）.顺铂组小鼠腹水中肿瘤细胞的凋亡率为（68.9±5.4）％,明显高于对照组（12.4±2.3）％和恩度组（11.0±3.8）％.恩度组小鼠的腹膜渗透性为（2.03±0.05） ng/mL,VEGF浓度为（23.7±3.0） ng/mL,MMP-2为（10.3±1.1） ng/mL,显著低于对照组和顺铂组.各组小鼠的肝肾功能未发现明显异常.结论 恩度联合顺铂治疗S180腹水瘤疗效显著,安全性好;其机制可能与恩度下调VEGF和MMP-2的表达及顺铂促进肿瘤细胞的凋亡有关.OBJECTIVE To study effect and safety of combination of recombinant human endostatin （endostar） and cisplatin in mice model bearing S180 tumor aseite, and investigate the potential mechanism. METHODS Tumor ascites models were established with S180 cells by intraperitoneal injection. 120 ICR mice were randomly assigned into four groups ： the control group （0.9 % NaCI, d1 - dl0 ）, the endostar group （endostar 8 mg/kg, d1 -- d5 , d7 -- d10 ; 0.9 % NaC1, d6 ） ,the cisp]atin group （ cisplatin 0. 04 mg/kg, d6 ; 0. 9% NaC1, d1 -- d5, d7 -- d10 ） and the combined group （ endostar 8 mg/kg,dl --d5 ,d7 --d10 ;cisplatin 0.04 mg/kg,d6 ）. Body mass,the volume of ascites,the number of tumor cells and red ceils as well as survival time were measured. The peritoneum permeability assay, blood routine,liver function and renal function were measured in each group respectively. Tumor cell apoptosis was detected by flow cytometry. The expression of vascular endothelial groth factor（VEGF） and matrix metalloproteinases 2 （MMP-2） was detected by ELISA. RESULTS In the combined group,the volume of ascites was （2. 1 ± 1.0） mL, the number of tumor cells was （10.6±2. 5） × 107 mL-1 ,and the number of red cells was （12.0±3.1） × 107 mL-1 ,which was lower than that in the other groups. The survival time of the combined group was 24. 1 d,which was longer than that of control group （12.7 d）,endostar group （16.8 d） and cisplatin group （18.9 d）. Tumor cell apoptosis of cisplatin group was （68.9±5.4）%,higher than those in control group（12.4±2.31）% and endostar group（11. 0±3.8）%. In the endostar group,the peritoneum permeability was （2.03±0.05） ng/mL,VEGF was （23. 74±3.0） ng/mL and MMP-2 was （10. 3±1. 1） ng/mL,which was lower than those in control group and cisplatin group. Blood routine,liver function and renal function of the each groups were normal. CONCLUSIONS The combination of endostar and cisplatin has better effect and the safety. The potential mechanism po

关 键 词：重组人血管内皮抑制素 顺铂 腹水 腹膜渗透性 血管内皮生长因子 基质金属蛋白酶2 

分 类 号：R730.53[医药卫生—肿瘤]