Evaluation of Adverse Cardiac Effects Induced by Arsenic Trioxide, a Potent Anti-APL Drug
Evaluation of Adverse Cardiac Effects Induced by Arsenic Trioxide, a Potent Anti-APL Drug
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DOI：
10.1615/jenvironpatholtoxicoloncol.v28.i3.60
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发表时间：
2009-01-01
影响因子：
2.4
通讯作者：
Bhadauria, Smrati
中科院分区：
文献类型：
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作者：
Raghu, K. G.;Yadav, Govind Kumar;Bhadauria, Smrati
三氧化二砷（ATO/As 2 O3）是治疗急性早幼粒细胞白血病（APL）复发患者的一种有前途的药物，但它经常导致致命的心律失常。本研究旨在探讨As_2O_3引起心脏不良反应的各种细胞和分子机制及其引起的电生理改变。我们显示ATO（0.2，0.4，0.8，1.6，3.2，6.4 μ M）对豚鼠乳头肌电驱动心脏动作电位的剂量依赖性效应。ATO在不同水平的复极、传导延迟和三角测量增加时导致动作电位时程（APD）显著延长，这是化合物促心律失常电位的新标志物。电解质失衡（低镁血症和低钾血症）也被发现会导致ATO毒性放大。由于离子通道在心脏动作电位的产生中起着非常重要的作用，我们使用了各种离子通道调节剂，如胆碱，米诺地尔，硝苯地平，维拉帕米，以确定这些药物是否可以拮抗ATO引起的电生理改变。在两个实验中，ATO给药动物10天导致心肌组织解体，间质水肿和心脏中炎性细胞浸润。还努力筛选维生素C对ATO毒性的功效。ATO还导致某些与心脏功能和抗氧化机制相关的临床酶活性显著增加，如血清肌酸激酶同工酶、乳酸脱氢酶、谷胱甘肽过氧化物酶和还原型谷胱甘肽。总之，ATO引起显著的心脏不良反应，我们建议在ATO治疗期间监测心功能。我们的研究结果还表明，身体的主要电解质含量（如镁和钾）的状态也是三氧化二砷毒性大小的影响因素。
Arsenic trioxide (ATO/As2O3) is a promising drug for patients with a relapse of acute promyelocytic leukemia (APL); however, it frequently causes fatal arrhythmias. This study aims to investigate the various cellular and molecular mechanisms of adverse cardiac effects and the elcctrophysiological alterations caused by As2O3. We show the dose-dependent effect of ATO (0.2, 0.4, 0.8, 1.6, 3.2, 6.4 mu M) on electrically driven cardiac action potential from the papillary muscle of the guinea pig. ATO causes a significant prolongation of action potential duration (APD) at various levels of repolarization, conduction delay, and increased triangulation, which is a novel marker for the proarrhythmic potential of a compound. Electrolyte imbalance (hypomagnesemia and hypokalemia) has also been found to cause amplification of ATO toxicity. Since ion channels play a very important role in the generation of cardiac action potential, we used various ion channel modulators such as choline, minoxidil, nifedipine, and verapamil to determine whether these agents could antagonize electrophysiological alterations caused by ATO. In in two experiments, ATO administration to animals for 10 days caused myocardial disorganization, interstitial edema and infiltration of inflammatory cells in the heart. Efforts were also made to screen the efficacy of vitamin C against ATO toxicity. ATO also caused a significant increase in the activity of certain clinically relevant enzymes for cardiac function and antioxidant mechanisms-such as serum creatine kinase isoenzyme, lactate dehydrogenase, glutathione peroxidase and reduced glutathione. In conclusion, ATO causes significant adverse cardiac effects and we suggest that cardiac function to be monitored during treatment with ATO. Our results also indicate that the status of the body's main electrolyte content (such as magnesium and potassium) is also an influencing factor on the magnitude of toxicity of arsenic trioxide.