Center for Translational Medicine and Cardiology Division, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Prog Cardiovasc Dis. 2010 Sep-Oct;53(2):114-20. doi: 10.1016/j.pcad.2010.06.006.
Cancer growth and metastasis are often driven by activating mutations in, or gene amplications of, specific tyrosine or serine/threonine kinases. Kinase inhibitors (KIs) promised to provide targeted therapy-specifically inhibiting the causal or contributory kinases driving tumor progression while leaving function of other kinases intact. These inhibitors are of 2 general classes: (1) monoclonal antibodies that are typically directed against receptor tyrosine kinases or their ligands and (2) small molecules targeting specific kinases. The latter will be the focus of this review. This class of therapeutics has had some remarkable successes, including revolutionizing the treatment of some malignancies (eg, imatinib [Gleevec] in the management of chronic myeloid leukemia) and adding significantly to the management of other difficult to treat cancers (eg, sunitinib [Sutent] and sorafenib [Nexavar] in the management of renal cell carcinoma). But in some instances, cardiotoxicity, often manifest as left ventricular dysfunction and/or heart failure, has ensued after the use of KIs in patients. Herein we will explore the mechanisms underlying the cardiotoxicity of small-molecule KIs, hoping to explain how and why this happens, and will further examine strategies to deal with the problem.
癌症的生长和转移通常是由特定的酪氨酸或丝氨酸/苏氨酸激酶的激活突变或基因扩增驱动的。激酶抑制剂（KIs）有望提供靶向治疗，特异性抑制导致肿瘤进展的因果或促成激酶，同时保持其他激酶的功能完整。这些抑制剂有 2 种一般类型：（1）针对受体酪氨酸激酶或其配体的单克隆抗体，（2）针对特定激酶的小分子。后者将是本综述的重点。这一类治疗药物取得了一些显著的成功，包括彻底改变了某些恶性肿瘤的治疗方法（例如伊马替尼[格列卫]治疗慢性髓性白血病），并显著改善了其他难以治疗的癌症的治疗方法（例如舒尼替尼[索坦]和索拉非尼[多吉美]治疗肾细胞癌）。但在某些情况下，在患者中使用 KIs 后会出现心脏毒性，通常表现为左心室功能障碍和/或心力衰竭。在此，我们将探讨小分子 KIs 心脏毒性的机制，希望解释这种情况发生的原因和机制，并进一步探讨解决该问题的策略。
