文章：

酪氨酸激酶抑制心脏毒性的分子机制

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

原文发布日期：2007-05-01

DOI: 10.1038/nrc2106

类型: Review Article

开放获取: 否

要点：

1. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several malignancies, converting lethal diseases into manageable, if not curable, chronic diseases. This makes it essential to limit toxicities of these agents.
2. The goal of tumour-cell killing by TKIs must be balanced against cardiotoxicity, because in some instances tumour cell death and preservation of cardiomyocyte health may be mutually exclusive.
3. Cardiomyocytes are contractile and have an extremely high demand for ATP. As a result, they might be particularly susceptible to agents that perturb mitochondrial function, either as a primary or secondary effect. Therefore, alterations in mitochondrial function could have a role in the cardiotoxicities of some currently approved agents.
4. Very few clinical trials have examined cardiotoxicities of TKIs in a prospective fashion with predefined cardiac endpoints, including left ventricular function. Therefore, there is a wide gap in our knowledge regarding the types of, and risk of, cardiotoxicity for most of these agents.
5. Some current kinase targets in cancer are not expressed in cardiomyocytes and therefore have little or no direct role in cardiomyocyte survival. However, the current generation of TKIs is inherently non-selective, and the purposeful design of multi-targeted TKIs might allow a single agent to be more effective, and to be used in more types of cancer, but with this comes an increased risk of cardiotoxicity. In some cases this will probably be due to inhibition of 'bystander' targets that are not essential for the killing of tumour cells but that are involved in cardiomyocyte survival.
6. Identification of the kinase that, when inhibited, is responsible for cardiotoxicity of an agent is important for future drug design, which should avoid these kinases where possible. Thus, greater selectivity of individual agents may require the use of more agents to treat a particular cancer, but cardiotoxicity as an 'off-target' effect should be minimized.

要点翻译：

1. 酪氨酸激酶抑制剂（TKI）彻底改变了多种恶性肿瘤的治疗模式，将致命性疾病转化为可控制的慢性疾病（即便尚未达到根治效果）。这使得限制此类药物的毒性作用变得至关重要。
2. TKI杀伤肿瘤细胞的目标必须与心脏毒性风险相权衡，因为在某些情况下，肿瘤细胞死亡与心肌细胞健康维持可能是相互排斥的。
3. 心肌细胞具有收缩功能，对ATP的需求极高。因此，它们可能特别容易受到干扰线粒体功能药物的影响（无论是原发性还是继发性效应）。目前获批的某些药物所致心脏毒性，可能与其改变线粒体功能有关。
4. 目前极少有临床试验采用预设心脏终点（包括左心室功能）对TKI的心脏毒性进行前瞻性研究。因此，我们对大多数TKI所致心脏毒性的类型和风险认知存在巨大空白。
5. 当前部分癌症治疗的激酶靶点并不在心肌细胞中表达，因此对心肌细胞存活几乎没有直接影响。但现有TKI本质上缺乏选择性，而多靶点TKI的定向设计虽可使单药疗效更强、适用癌种更广，却会伴随心脏毒性风险的增加。某些情况下，这可能是由于抑制了"旁观者"靶点——这些靶点对肿瘤细胞杀伤非必需，却参与心肌细胞的存活过程。
6. 明确导致药物心脏毒性的特定激酶靶点对未来药物设计至关重要，应尽可能规避这些激酶。因此，虽然提高单药选择性可能需要联合使用更多药物治疗特定癌症，但作为"脱靶"效应的心脏毒性应当被最小化。

英文摘要：

Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of 'targeted therapies', particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.

摘要翻译： 

癌症治疗近年来取得了显著进展，其中“靶向治疗”的发展尤为突出，特别是使用抑制某些酪氨酸激酶活性的药物。这些酪氨酸激酶的激活突变或扩增是肿瘤发生的原因，或对其有重要贡献。然而，其中一些疗法与心脏毒性相关。在此，我们总结了关于靶向酪氨酸激酶的癌症药物心脏毒性的已知信息。我们重点关注特定信号通路中断导致心肌细胞功能障碍和/或死亡的基本机制，并将其与癌细胞中的治疗反应进行对比。

原文链接：

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition