康艾注射液对曲妥珠单抗心肌毒性的抑制作用及机理研究  

Research on the Mechanism of Kang’ai Injection Mitigating Cardiotoxicity Induced by Trastuzumab

作　　者：周捷[1] 何伟佳[1] 杜宝萍 刘海 刘庆[1] 巫玮 曹成明 ZHOU Jie;HE Weijia;DU Baoping;LIU Hai;LIU Qing;WU Wei;CAO Chengming(Sun Yat-sen University Cancer Center,Guangzhou,Guangdong 510060,China;Guangdong Food and Drug Vocational-technical School,Guangzhou,Guangdong 501663,China;Guangzhou Office of Shanghai Roche Pharmaceutical Co.Ltd.,Guangzhou,Guangdong 510055,China)

机构地区：[1]中山大学肿瘤防治中心,广东广州510060 [2]广东省食品药品职业技术学校,广东广州501663 [3]上海罗氏制药有限公司广州办事处,广东广州510055

出　　处：《今日药学》2020年第3期168-171,193,共5页Pharmacy Today

基　　金：广东省中医药局项目(20161062)。

摘　　要：目的研究康艾注射液对曲妥珠单抗所致心肌毒性的抑制作用和机制。方法将50只雌性SD大鼠随机分为1个对照组(n=10)、1个模型组(n=10)和3个研究组(n=10),模型组隔天一次经尾静脉注射曲妥珠单抗(50.4 mg·kg^-1)造模,共注射7次;研究组造模后按低、中、高三个剂量10,20,30 mL·kg^-1隔天2次注射康艾注射液,共处理7 d;对照组连续14 d注射相应体积的曲妥珠单抗专用溶剂。各组大鼠均利用超声影像仪检查心功能变化,通过测定血清中肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)、心肌肌钙蛋白I(cTnI)、N末端钠尿肽原(NT-pro BNP)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)的浓度评价心肌受损的程度;ELISA法检测心肌组织中Bcl-2、Bax的表达量,酶解荧光法和比色法分别检测Calpain-1(钙蛋白酶)和Caspase-3的活性,研究康艾注射液保护心肌细胞机制;检测丙二醛(MDA)的含量和超氧化物歧化酶(SOD)的活性考察心肌氧化应激的情况。结果与模型组相比,研究组大鼠左室射血分数(LVEF)、左室短轴缩短率(LVFS)均显著较高(P<0.05);血清中CK-MB、LDH、cTnI、NT-pro BNP、TNF-α、IL-6的含量、心肌细胞中Bax的表达量、生成MDA的水平以及Calpain-1和Caspase-3的活性均显著低于模型组(P<0.05),与此同时Bcl-2的表达量和SOD的活性均显著高于模型组(P<0.05),各项指标变化均与康艾注射液剂量呈正相关性。结论康艾注射液可降低曲妥珠单抗所致的心肌毒性,其机制可能是通过改善心肌血液供应,抑制炎症反应、钙离子超载,低氧化应激损伤发挥保护心肌细胞的作用。OBJECTIVE To study the inhibitory effect and mechanism of Kang’ai injection on myocardial toxicity induced by trastuzumab.METHODS Fifty female SD rats were randomly divided into one control group(n=10),one model group(n=10)and three research groups(n=10).The model group was injected with trastuzumab(50.4 mg·kg-1),qod,7 times,through caudal vein.The study groups were injected with Kang’ai injection at low,medium and high doses of 10,20 and 30 mL·kg-1,q12h for 7 days.The control group was injected with specific solvent of trastuzumab of corresponding volume for 14 days.The changes of cardiac function were examined by ultrasonography.The degree of myocardial injury was assessed by the concentration of creatine kinase isoenzymes(CK-MB),lactate dehydrogenase(LDH),cardiac troponin I(cTnI),N-terminal natriuretic peptide(NT-pro BNP)and tumor necrosis factor-alpha(TNF-alpha).The expression of Bcl-2 and Bax in myocardium was detected by ELISA,and the expression of Bcl-2 and Bax in myocardium was detected by enzymatic hydrolysis fluorescence method.Calpain-1 and Caspase-3 were detected by colorimetry to study the protective mechanism of Kang’ai injection on myocardial cells.Malondialdehyde(MDA)content and superoxide dismutase(SOD)activity were measured to investigate the oxidative stress of myocardium.RESULTS Compared with the model group,the left ventricular ejection fraction(LVEF)and left ventricular short axis shortening rate(LVFS)in the study group were significantly higher(P<0.05).The serum levels of CK-MB,LDH,cTnI,NT-pro BNP,TNF-alpha,the expression of Bax in myocardial cells,the level of MDA production and the activity of Calpain-1 and Caspase-3 were significantly lower than those in the model group(P<0.05).The activity of D was significantly higher than that of model group(P<0.05).The changes of each index were positively correlated with the dosage of Kang'ai injection.CONCLUSION Kang'ai injection can reduce the myocardial toxicity induced by trastuzumab.Its mechanism may be related to the protection of myoc

关 键 词：康艾注射液 曲妥珠单抗 人类表皮生长因子受体-2 心肌毒性 

分 类 号：R969.2[医药卫生—药理学]