聚合人脐带血血红蛋白氧载体增强仑伐替尼对肝癌移植瘤裸鼠疗效的初步实验  

Efect of PolyCHb on enhancing tissue oxygen supply and the treatment of remvatinib for liver cancer graft: Preliminary observation

作　　者：董德操 高燚秋 王红[1] 李燊[1] 刘嘉馨[1] DONG Decao;GAO Yiqiu;WANG Hong;Li Shen;LIU Jiaxin(Institute of Blood Transfusion,Chinese A-cadenvy of Medical Sciences and Peking Union Medical College,Chengdu 610065,China)

机构地区：[1]中国医学科学院北京协和医学院输血研究所,四川成都610065

出　　处：《中国输血杂志》2021年第5期456-460,共5页Chinese Journal of Blood Transfusion

基　　金：中国医学科学院医学与健康科技创新工程(2017-I2M-3-021,2016-I2M-1-018)。

摘　　要：目的探讨输注聚合人脐带血血红蛋白氧载体(PolyCHb)增强肝癌荷瘤裸鼠对仑伐替尼治疗敏感性的作用机制。方法建立Hep3B肝癌细胞系裸鼠皮下移植瘤模型,将18只荷瘤小鼠随机均分为对照组:生理盐水灌胃90 mg·kg -1·d^(-1);单药组:仑伐替尼灌胃10 mg·kg^(-1)·d^(-1);增敏组:仑伐替尼灌胃10 mg·kg^(-1)·d^(-1),PolyCHb尾静脉注射600 mg·kg^(-1),2次/周;3组均连续给药28 d,定时测量肿瘤体积、绘制肿瘤生长曲线,在29 d处死裸鼠,剥瘤称取肿瘤重量并做苏木精-伊红染色法(HE)切片评价各组肿瘤的病理形态学;免疫组化(IHC)法测定各组肿瘤组织中缺氧诱导因子(HIF-1α)、CD34、血管内皮生长因子(VEGF)、CD44、基质金属蛋白酶9(MMP-9)、葡萄糖转运蛋白1 (GLUT-1)的表达量;二氢乙锭法测定各组肿瘤组织中活性氧(ROS)的含量。结果 29 d(给药28 d结束后24 h),对照组、单药组及增敏组分别为肝癌荷瘤裸鼠肿瘤体积(mm3):2 076.46±350.25 vs 1 035.96±84.16 vs 892.66±104.46(P<0.05);肿瘤重量(g):1.61±0.52 vs 0.45±0.10 vs 0.34±0.13(P<0.05);IHC评分(分):HIF-1α分别为75±23 vs 45±18 vs 18±11,VEGF分别为52±8 vs 67±16 vs 35±4,CD34分别为40±7 vs 50±13 vs 28±7,CD44分别为37±15 vs 30±7 vs 15±3,GLUT-1分别为74±41 vs 51±30 vs 14±18,MMP-9分别为51±7 vs 62±20 vs 33±3(均为P<0.05);HE切片染色评价:增敏组的肿瘤恶性程度明显低于单药组和对照组;肿瘤组织的ROS含量评价:增敏组较单药组、对照组有所提高。结论 PolyCHb的氧合作用,降低了裸鼠肝癌移植瘤模型中HIF-1α及其下游通路相关分子的表达,在一定时间内延缓了肿瘤生长,提升增强了仑伐替尼的疗效。Objective To investigate the effect of Polymerized human cord hemoglobin(PolyCHb) on the sensitivity of hepatocellular carcinoma grafts to lumvalatinib in nude mice. Methods Hep3 B hepatoma cells were subcutaneously transplanted in 18 nude mice to establish tumor graft model. Mice were randomly divided into 3 groups: control group(the saline 90 mg·kg^(-1)·d^(-1)), monotherapy group(Lenvatinib10 mg·kg^(-1)·d^(-1)), and sensitized group(Lenvatinib mg·kg^(-1)·d^(-1), polyCHB 600 mg/kg twice a week) for 28 days. The tumor volume was measured regularly and the growth curve was drawn. On day 29, the nude mice were sacrificed, the tumor was stripped and weighed, and the pathomorphological differences of each group were evaluated by HE section staining. The expression levels of hypoxia-inducing factor(HIF-1α), CD34, VEGF, CD44, MMP-9, and Glut-1 in tumor tissues of each group were determined by immunohistochemistry. The content of reactive oxygen species(ROS) in tumor tissues of each group was determined by dihydroethyl ingot method.Results The tumor growth rate and tumor volume in the sensitized group decreased significantly compared with the control group and the solo drug group. On day 29, the tumor volumes of the control group, the monotherapy group and the sensitization group were(2 076.46±350.25)mm3,(1 035.96±84.16)mm3 and(892.66±104.46)mm3, respectively. Tumor weight was(1.61±0.52)g,(0.45±0.10)g, and(0.34±0.13)g, respectively. Immunohistochemical score of HIF-1α was 75±23 vs 45±18 vs 18±11, VEGF was 52±8 vs 67±16 vs 35±4, CD34 was 40±7 vs 50±13 vs 28±7, CD44 was 37±15 vs 30±7 vs 15±3, Glut-1 was 74±41 vs 51±30 vs 14±18, MMP-9 was 51±7 vs 62±20 vs 33±3, respectively(P<0.05). The malignant degree of the sensitized group was decreased by HE section staining, which was significantly lower than that of the solo drug group and the control. The ROS content in the sensitized group was higher than that in the solo drug group and the control. Conclusion PolyCHb can reduce the expression of HI

关 键 词：血红蛋白氧载体 人脐带血 仑伐替尼 肝癌移植瘤 裸鼠 缺氧诱导因子(HIF)-1α 红细胞代用品 动物实验 

分 类 号：R457.1[医药卫生—治疗学] R737.5[医药卫生—临床医学]