系統識別號 U0026-1807201916444200
論文名稱(中文) 拉帕替尼(lapatinib)與索拉非尼(sorafenib) 對於心臟細胞上不同離子電流的區別性抑制作用
論文名稱(英文) Differential inhibitory actions by lapatinib or sorafenib, known as multi-targeted tyrosine kinase inhibitors, on different types of ionic currents in heart cells
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 107
學期 2
出版年 108
研究生(中文) 李凱森
研究生(英文) Kai-Sen Lee
學號 S36061072
學位類別 碩士
語文別 英文
論文頁數 48頁
口試委員 指導教授-吳勝男
中文關鍵字 酪胺酸激酶抑制劑  鉀離子電流  鈉離子電流  動作電位持續時間  心臟細胞 
英文關鍵字 Tyrosine kinase inhibitor  K+ currents  Na+ current  action potential duration  heart cell 
中文摘要 拉帕替尼(lapatinib)與索拉非尼(sorafenib)是一種酪胺酸激酶抑制劑。透過其抑制作用影響細胞下游信號,抑制腫瘤細胞的生長和血管新生,近來被核准使用於癌症治療。然而此類藥物存在著副作用,其中一項為心律不整。在先前的研究指出,有些患者服用此類酪胺酸激酶抑制劑後心電圖中出現QT間隔延長的現象。QT延長有很高機率會導致tosade de pointes這個多型性心室心搏過速,可能會導致暈眩甚至是猝死。在過去的研究當中,緩慢激活延遲修正的鉀離子電流(slowly activating delayed-rectifier K+ current)與erg調控的鉀離子電流(erg-mediated K+ current)的表現能夠影響心電圖QT間隔的時間長短。然而此類酪胺酸激酶抑制劑對心臟細胞膜上是否產生影響目前還是未知的。在本篇研究中我們利用細胞膜箝制的技術(patch-clamp),評估拉帕替尼與索拉非尼這類酪胺酸激酶抑制劑對於心臟細胞(H9c2和neonatal rat ventricular cardiomyocytes)上離子電流的影響。包含緩慢激活延遲修正的鉀離子電流、erg調控的鉀離子電流、向內修正鉀離子電流(inwardly rectifying K+ current)和電壓門控的鈉離子電流(voltage-gated Na+ current)。研究結果顯示,在給予藥物後緩慢激活延遲修正的鉀離子電流的振幅會受到抑制,此電流動力學也會受到影響。給予藥物後也會讓此電流的活化曲線朝向更去極化電位移動,而曲線的門控電荷並沒有顯著變化。另外也發現此類藥物也會對erg調控的鉀離子電流、向內修正鉀離子電流和電壓門控的鈉離子電流有不同程度的抑制作用。在給予這類藥物後,心臟細胞的動作電位持續時間也會延長。綜合實驗的結果,此類藥物對於心臟細胞中離子通道具有臨床相關性,且可能有直接作用。
英文摘要 Lapatinib (LAP) and sorafenib (SOR) are multi-targeted, small molecules which belong to a family of tyrosine kinase inhibitors (TKIs). They have been recently approved for the treatment of a variety of malignant cancers. They are recognized to influence the signaling pathway of tumor cell proliferation, and to inhibit cell surface kinases, thus decreasing the angiogenesis. However, some TKIs have been notably reported to cause a significant prolongation of electrocardiographic QTc interval. The prolongation of QTc intervals may cause the tosade de pointes tachyarrhythmia, which may result in syncope or sudden death. Previous studies have shown that changes in the amplitude and kinetics of the slowly activating delayed-rectifier K+ current IK(S) and erg-mediated K+ current IK(erg) can potentially alter the QT interval duration. Therefore, in this study, we wanted to evaluate the possible effects of LAP or SOR on ionic currents including IK(S), IK(erg), inwardly rectifying K+ current IK(IR), voltage-gated Na+ current (INa) in heart-derived H9C2 cells and in neonatal rat ventricular cardiomyocytes by using the patch-clamp technique. Findings from these results have shown that the presence of LAP or SOR was able to suppress IK(S) amplitude as well as to alter the IK(S) activation and deactivation time courses. The presence of LAP can also shift the activation curve of IK(S) towards more depolarized potentials with no significant change in gating charge of the curve. Therefore, the presence of LAP or SOR can directly suppress the amplitudes of IK(S), IK(erg) , IK(IR) and INa with different potency observed in heart cells. Addition of LAP or SOR can also cause the prolongation of action potential duration. The targets for these ion channels in heart cells tend to be direct and could be of clinical relevance for this group of drugs, if similar findings occur in vivo.
論文目次 Table of Contents I
Figure Contents II
中文摘要 1
Abstract 2
Acknowledgement 4
Introduction 5
Materials and Methods 8
Chemicals and solutions 8
Cell preparations 9
Isolation and culture of neonatal rat ventricular myocytes 10
Electrophysiological measurements 10
Data analyses 12
Statistical analysis 12
Kinetic study of LAP or SOR effect on the slow component of IK(S) deactivation time course 13
Results 15
Effect of high K+ solution on K+ current in H9c2 cells 15
Concentration-dependent effects of LAP or SOR on IK(S) in H9c2 cells 16
Effect of LAP on the I-V relationship of IK(S) in H9c2 cells 18
Effect of LAP and LAP plus VEGF on IK(S) in H9c2 cells. 19
Inhibitory effect of LAP on IK(S) elicited by a train of rapid repetitive depolarizations 19
Effect of LAP in erg-mediated K+ current (IK(erg)) in H9c2 cells 20
Suppressive effect of LAP and SOR on IK(IR) amplitude measured from cultured neonatal rat ventricular myocytes 21
Effect of LAP on voltage-gated Na+ current (INa) in cultured neonatal rat ventricular myocytes 21
Effect of LAP on membrane potential recorded from cultured neonatal rat ventricular myocytes 22
Discussion 24
References 28
Figures 35
Figure Legends 44

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