Schneider J W, Chang A Y, Rocco T P
Division of Cardiology, Department of Medicine, VA Boston Healthcare System and Harvard Medical School, West Roxbury, MA 02132, USA.
Semin Oncol. 2001 Oct;28(5 Suppl 16):18-26. doi: 10.1016/s0093-7754(01)90278-7.
Cardiotoxicity is a common and potentially devastating side effect of antineoplastic drug therapy. This empiric observation is seen as paradoxical given that the cardiomyocyte is considered to be a terminally differentiated cell. Despite the fact that these cells do not divide after birth, adult cardiomyocytes may become "innocent bystander" targets of anticancer drugs designed to interfere with cell signaling pathways in rapidly proliferating cells. In breast cancer clinical trials, treatment with the erbB2 receptor antibody trastuzumab combined with anthracyclines has been associated with an increased risk for the development of cardiac pump failure. Trastuzumab/anthracycline cardiomyopathy may be the first clinically significant cardiotoxicity to emerge from signal transduction therapeutics. The erbB2 receptor tyrosine kinase is known to have a critical role in cardiac development. In addition, erbB2 is thought to participate in an important pathway for growth, repair, and survival of adult cardiomyocytes as part of a signaling network that involves neuregulins and the neuregulin receptor erbB4. However, erbB2 levels in the adult heart are low when compared with the levels found in erbB2-overexpressing breast cancer cells that are the intended targets of trastuzumab therapy. Thus, trastuzumab-associated cardiotoxicity must be explained by some alternative mechanism. After confirming that trastuzumab is capable of inducing tyrosine phosphorylation of the human cardiomyocyte erbB2 protein, a novel system for culturing human myocardium was developed in our laboratory. We used this system to study the effects of trastuzumab on human cardiomyocytes in vitro and observed trastuzumab-induced structural and functional changes in human cardiomyocytes that were at least partially reversible with the addition of recombinant neuregulins. The results obtained in these experiments support a direct action of trastuzumab on human cardiomyocytes. In addition, these data provide insight regarding potential molecular mechanisms. Most importantly, these data draw attention to the inherent risk of cardiotoxicity associated with a newly emerging class of antineoplastic drugs that interfere with signal transduction pathways.
心脏毒性是抗肿瘤药物治疗常见且可能具有毁灭性的副作用。鉴于心肌细胞被认为是终末分化细胞，这一经验性观察结果显得自相矛盾。尽管这些细胞出生后不再分裂，但成年心肌细胞可能会成为旨在干扰快速增殖细胞中细胞信号通路的抗癌药物的“无辜旁观者”靶点。在乳腺癌临床试验中，使用erbB2受体抗体曲妥珠单抗联合蒽环类药物治疗与发生心脏泵衰竭的风险增加相关。曲妥珠单抗/蒽环类药物所致心肌病可能是信号转导治疗中首个出现的具有临床意义的心脏毒性。已知erbB2受体酪氨酸激酶在心脏发育中起关键作用。此外，erbB2被认为作为涉及神经调节蛋白和神经调节蛋白受体erbB4的信号网络的一部分，参与成年心肌细胞生长、修复和存活的重要途径。然而，与曲妥珠单抗治疗的目标——erbB2过表达乳腺癌细胞中的水平相比，成年心脏中的erbB2水平较低。因此，曲妥珠单抗相关的心脏毒性必须通过某种替代机制来解释。在证实曲妥珠单抗能够诱导人心肌细胞erbB2蛋白的酪氨酸磷酸化后，我们实验室开发了一种用于培养人心肌的新系统。我们使用该系统在体外研究曲妥珠单抗对人心肌细胞的影响，并观察到曲妥珠单抗诱导的人心肌细胞结构和功能变化，添加重组神经调节蛋白后这些变化至少部分可逆。这些实验获得的结果支持曲妥珠单抗对人心肌细胞的直接作用。此外，这些数据提供了有关潜在分子机制的见解。最重要的是，这些数据提醒人们注意与一类新出现的干扰信号转导通路的抗肿瘤药物相关的固有心脏毒性风险。
