The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia 'torsades de pointes', which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.

中文翻译：

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目前对药物诱导的QT延长及其对抗癌治疗的意义的理解。

QT间隔是心室复极化的整体指标，在个体之间会有所不同，并且受各种生理和病理生理刺激（例如性别，年龄，心率，电解质浓度，伴随性心脏病和其他疾病，例如糖尿病）的影响。许多药物对QT间隔产生很小但可重现的作用，但在极少数情况下，这种现象被夸大了，而且明显的QT延长可引起多形性室性心动过速“尖锐湿疣”，可导致晕厥或心源性猝死。药物延长QT的普遍接受的普遍机制是心脏中关键的复极化钾电流IKr的阻断，IKr是通过表达KCNH2（也称为HERG）而产生的。因此，对新药实体可能会导致尖端扭转型室速的可能性的评估依赖于正常志愿者或患者在正常和高浓度下接触药物，以及体外IKr阻滞的评估。最近的工作集中在具有QT延长责任的抗癌药物上，它正在定义药物延长QT的新途径。值得注意的是，某些酪氨酸激酶抑制剂延长心脏动作电位（QT的细胞相关性）的体外作用可以通过胞内磷脂酰肌醇3,4,5-三磷酸磷酸酯（磷酸肌醇3激酶的下游效应物）来挽救。这一发现支持直接或通过抑制上游激酶来抑制该酶的作用，从而通过正在研究的机制延长QT，但包括增强的内向“晚期” 动作电位处于平台期的钠电流。非IKr依赖的QT延长途径的定义对于评估风险非常重要，这不仅是评估抗癌疗法，而且是使用其他QT延长药物的风险，以及对细胞内信号传导系统的可变活性如何调节QT和相关心律失常的精确理解风险。