Force Thomas, Kerkelä Risto
Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107, USA.
Drug Discov Today. 2008 Sep;13(17-18):778-84. doi: 10.1016/j.drudis.2008.05.011. Epub 2008 Sep 2.
Cardiotoxicity of some targeted therapeutics, including monoclonal antibodies and small-molecule inhibitors, is a reality. Herein we will examine why it occurs, focusing on molecular mechanisms to better understand the issue. We will also examine how big the problem is and, more importantly, how big it may become in the future. We will review models for detecting cardiotoxicity in the preclinical phase. We will also focus on two key areas that drive cardiotoxicity: multitargeting and the inherent lack of selectivity of ATP-competitive antagonists. Finally, we will examine the issue of reversibility and discuss possible approaches to keeping patients on therapy.
包括单克隆抗体和小分子抑制剂在内的一些靶向治疗药物的心脏毒性是一个现实问题。在此，我们将探讨其发生的原因，重点关注分子机制以更好地理解该问题。我们还将研究这个问题的严重程度，更重要的是，它在未来可能会变得多严重。我们将回顾临床前阶段检测心脏毒性的模型。我们还将聚焦于导致心脏毒性的两个关键领域：多靶点作用以及ATP竞争性拮抗剂固有的选择性缺乏。最后，我们将研究可逆性问题，并讨论让患者持续接受治疗的可能方法。
