Chaar Maher, Kamta Jeff, Ait-Oudhia Sihem
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA,
Onco Targets Ther. 2018 Sep 25;11:6227-6237. doi: 10.2147/OTT.S170138. eCollection 2018.
The tyrosine kinase inhibitor (TKI) drug class is a prominently used option in the treatment of various cancers. Safety evaluation of these drugs has shown evidence of cardiotoxicity of varying frequency and severity between agents; concern has led to updated labeling, warning prescribers of such. This review seeks to clarify the present dangers and investigate cardiotoxic mechanisms of action for each discussed TKI. Dasatinib was connected primarily with an incidence of fluid retention, edema, QT prolongation, and pulmonary hypertension in clinical studies. It is theorized that this is due to a combination of off-target kinase binding and on-target binding of Bcr-Abl, and less likely, mitochondrial induced apoptosis. Studies showed sorafenib to carry the risk of hypertension, QT prolongation, and myocardial infarction. Proposed mechanisms for these side effects include inhibition of proteins, vascular endothelium growth factor receptor, hERG potassium channels, and the RAF/MERK/ERK pro-survival pathway. Finally, lapatinib showed evidence of decreased left ventricular ejection fraction (LVEF) and QT prolongation in clinical studies. The literature attributes these as side effects of on-target ErbB2 binding leading to mitochondrial induced apoptosis. The concern warranted by these findings is in question. Pooled safety data suggest that the overall risk for cardiotoxicity is minimal in dasatinib and lapatinib. Sorafenib seems to carry a moderate concern. For the discussed agents, recommendations agree that routine monitoring via methods such as electroencephalogram, cardiac biomarkers, and blood pressure is warranted during the course of treatment, in addition to a comprehensive collection of past medical history and risk factors to identify those at heightened risk for cardiovascular events.
酪氨酸激酶抑制剂（TKI）药物类别是治疗各种癌症的常用选择。对这些药物的安全性评估表明，不同药物之间存在频率和严重程度各异的心脏毒性证据；这一问题已导致标签更新，警告开处方者注意此类情况。本综述旨在阐明当前的危险，并研究每种所讨论的TKI的心脏毒性作用机制。在临床研究中，达沙替尼主要与液体潴留、水肿、QT间期延长和肺动脉高压的发生率相关。据推测，这是由于脱靶激酶结合和Bcr-Abl的靶向结合共同作用，而线粒体诱导的细胞凋亡可能性较小。研究表明，索拉非尼有导致高血压、QT间期延长和心肌梗死的风险。这些副作用的推测机制包括对蛋白质、血管内皮生长因子受体、hERG钾通道以及RAF/MERK/ERK促生存途径的抑制。最后，在临床研究中，拉帕替尼显示出左心室射血分数（LVEF）降低和QT间期延长的证据。文献将这些归因于靶向ErbB2结合导致线粒体诱导的细胞凋亡的副作用。这些发现引发的担忧值得探讨。汇总的安全数据表明，达沙替尼和拉帕替尼的心脏毒性总体风险极小。索拉非尼似乎存在一定程度的担忧。对于所讨论的药物，建议一致认为，在治疗过程中，除了全面收集既往病史和风险因素以识别心血管事件高风险人群外，还应通过脑电图、心脏生物标志物和血压等方法进行常规监测。
