Sterba Martin, Popelová Olga, Simunek Tomás, Mazurová Yvona, Potácová Anna, Adamcová Michaela, Kaiserová Helena, Ponka Premysl, Gersl Vladimír
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Simkova 870, Hradec Králové 1, 500 38, Czech Republic.
J Pharmacol Exp Ther. 2006 Dec;319(3):1336-47. doi: 10.1124/jpet.106.111468. Epub 2006 Sep 26.
Iron chelation is the only pharmacological intervention against anthracycline cardiotoxicity whose effectiveness has been well documented both experimentally and clinically. In this study, we aimed to assess whether pyridoxal 2-chlorobenzoyl hydrazone (o-108, a strong iron chelator) can provide effective protection against daunorubicin (DAU)-induced chronic cardiotoxicity in rabbits. First, using the HL-60 leukemic cell line, it was shown that o-108 has no potential to blunt the antiproliferative efficacy of DAU. Instead, o-108 itself moderately inhibited cell proliferation. In vivo, chronic DAU treatment (3 mg/kg weekly for 10 weeks) induced mortality (33%), left ventricular (LV) dysfunction, a troponin T rise, and typical morphological LV damage. In contrast, all animals treated with 10 mg/kg o-108 before DAU survived without a significant drop in the LV ejection fraction (63.2 +/- 0.5 versus 59.2 +/- 1.0%, beginning versus end, not significant), and their cardiac contractility (dP/dt(max)) was significantly higher than in the DAU-only group (1131 +/- 125 versus 783 +/- 53 kPa/s, p < 0.05), which corresponded with histologically assessed lower extent and intensity of myocardial damage. Although higher o-108 dose (25 mg/kg) was well tolerated when administered alone, in combination with DAU it led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality. In conclusion, we show that shielding of free intracellular iron using a potent lipophilic iron chelator is able to offer a meaningful protection against chronic anthracycline cardiotoxicity. However, this approach lost its potential with the higher chelator dose, which suggests that iron might play more complex role in the pathogenesis of this disease than previously assumed.
铁螯合是针对蒽环类药物心脏毒性的唯一一种其有效性已在实验和临床中得到充分证明的药物干预措施。在本研究中，我们旨在评估吡哆醛2 - 氯苯甲酰腙（o - 108，一种强效铁螯合剂）是否能有效保护兔子免受柔红霉素（DAU）诱导的慢性心脏毒性。首先，使用HL - 60白血病细胞系表明，o - 108没有削弱DAU抗增殖效力的潜力。相反，o - 108本身适度抑制细胞增殖。在体内，慢性DAU治疗（每周3 mg/kg，共10周）导致死亡率（33%）、左心室（LV）功能障碍、肌钙蛋白T升高以及典型的左心室形态损伤。相比之下，在DAU治疗前用10 mg/kg o - 108治疗的所有动物均存活，左心室射血分数无显著下降（开始时为63.2±0.5%，结束时为59.2±1.0%，无显著差异），并且它们的心脏收缩力（dP/dt(max)）显著高于仅接受DAU治疗的组（1131±125与783±53 kPa/s，p < 0.05），这与组织学评估的心肌损伤程度和强度较低相对应。尽管单独给予较高剂量的o - 108（25 mg/kg）耐受性良好，但与DAU联合使用时，在心脏保护和总体死亡率方面导致了相当矛盾且大多为负面的结果。总之，我们表明使用强效亲脂性铁螯合剂屏蔽细胞内游离铁能够为慢性蒽环类药物心脏毒性提供有意义的保护。然而，这种方法在螯合剂剂量较高时失去了其潜力，这表明铁在该疾病发病机制中的作用可能比之前假设的更为复杂。
