中国组织工程研究2024，Vol.28Issue(27)：4265-4272,8.DOI:10.12307/2024.560
抗肿瘤药物开发中体外心脏的安全性风险评估
Safety risk assessment of in vitro heart in antitumor drug development
摘要
Abstract
BACKGROUND:Tyrosine kinase inhibitors,as well as other types of small-molecule cancer drugs,can cause severe cardiotoxicity. OBJECTIVE:To perform a heart safety re-evaluation by observing the effects of antitumor drugs on isolated heart electrocardiograph,cardiac action potential and associated ion channels and cytotoxicity. METHODS:Extracorporeal cardiac perfusion was given to the isolated rabbit heart using Langendorff perfusion:Sunitinib(0.3,3,10 μmol/L),Crizotinib(0.3,1,3 μmol/L),and Doxorubicin(1,30 μmol/L)were perfused sequentially for 120 minutes to record electrocardiograph and left ventricular pressure.A blank control group was set for comparison.Manual patch clamp was used to record the effects of Crizotinib,Sunitinib,Doxorubicin on hERG,Cav1.2,Nav1.5 channel currents and action potential in human induced pluripotent stem cell derived cardiomyocytes.Adenosine triphosphate level in human induced pluripotent stem cell derived cardiomyocytes was detected by CellTiter-Glo luminescent cell viability assay. RESULTS AND CONCLUSION:Isolated rabbit heart using Langendorff perfusion:Compared with the blank ontrol group,Sunitinib and Crizotinib at≥3 μmol/L decreased heart rate(P<0.01)and prolonged QT/QTc interval(P<0.01),and reduced left ventricular pressure to different extents.Manual patch clamp recording:Compared with the blank control group,Sunitinib and Crizotinib at 3 μmol/L inhibited the activities of hERG,Nav1.5 and Cav1.2 channels and significantly prolonged the duration of action potential(P<0.01).According to the analysis of the test article,the difference between the labeled concentration and the measured concentration of the recovered solution was not significant.Cell viability assays:Compared with the blank control group,adenosine triphosphate content in human induced pluripotent stem cell derived cardiomyocytes significantly decreased after treatment with Sunitinib(IC50=4.64 μmol/L),Doxorubicin(IC50=4.21 μmol/L)and Crizotinib(IC50=2.87 μmol/L),indicating that cell viability significantly decreased(P<0.01).To conclude,this study successfully established an early cardiac safety evaluation method for antitumor drugs,which provides good support and help for the subsequent development of antitumor drugs.关键词
舒尼替尼/克唑替尼/多柔比星/体外心脏灌流/电生理膜片钳/心脏安全评价Key words
Sunitinib/Crizotinib/Doxorubicin/Langendorff/patch clamp/cardiac safety evaluation分类
医药卫生引用本文复制引用
郑双佳,赵婷,任翠霞,王保强,陈兰兰,林沫旭,李英骥,张旭..抗肿瘤药物开发中体外心脏的安全性风险评估[J].中国组织工程研究,2024,28(27):4265-4272,8.基金项目
北京市科委科技计划资助项目(Z211100002521003),项目负责人:李英骥 Beijing Municipal Science and Technology Commission Science and Technology Program,No.Z211100002521003(to LYJ) （Z211100002521003）
