Razmaraii Nasser, Babaei Hossein, Mohajjel Nayebi Alireza, Asadnasab Gholamreza, Ashrafi Helan Javad, Azarmi Yadollah
*Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; †Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; ‡School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; §Department of Clinical Sciences, Tabriz Branch, Islamic Azad University, Tabriz, Iran; and ¶School of Veterinary, Tabriz University, Tabriz, Iran.
J Cardiovasc Pharmacol. 2016 Mar;67(3):237-45. doi: 10.1097/FJC.0000000000000339.
Doxorubicin (DOX) is an effective anticancer agent, but adverse cardiotoxic effects limit its use. Compounds reducing DOX cardiotoxicity could improve its therapeutic index. This study investigated the protective effects of phenytoin (Phen) for DOX-induced cardiomyopathy. Male Wistar rats were randomized into 5 groups to receive either saline, DOX (2 mg/kg per 48 hours, 6 doses, intraperitoneally) or DOX + Phen (5, 10, or 20 mg/kg/d, starting 4 days before DOX, intraperitoneally). The animals were assessed 24 hours after the last injection. Left ventricular (LV) function and hemodynamic parameters were assessed using transthoracic echocardiography, electrocardiography, and a Millar pressure catheter. Histopathological studies were performed, and the effect of Phen on the cytotoxicity of DOX was evaluated in vitro for the human breast adenocarcinoma cell line. DOX-impaired LV function significantly decreased the LV systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening, and contractility index. DOX caused structural changes in myocardial cells. Treatment with Phen decreased DOX-induced toxicity, significantly improved ventricular function, and ameliorated structural changes in the myocardium. Phen also did not interfere with the antitumor effect of DOX. The results confirm the cardioprotective effect of Phen against DOX-induced cardiomyopathy without removing antitumor effect of DOX.
阿霉素（DOX）是一种有效的抗癌药物，但不良心脏毒性作用限制了其使用。能够降低DOX心脏毒性的化合物可提高其治疗指数。本研究调查了苯妥英（Phen）对DOX诱导的心肌病的保护作用。将雄性Wistar大鼠随机分为5组，分别接受生理盐水、DOX（每48小时2 mg/kg，共6剂，腹腔注射）或DOX + Phen（5、10或20 mg/kg/d，在DOX给药前4天开始，腹腔注射）。在最后一次注射后24小时对动物进行评估。使用经胸超声心动图、心电图和Millar压力导管评估左心室（LV）功能和血流动力学参数。进行组织病理学研究，并在体外评估Phen对人乳腺腺癌细胞系DOX细胞毒性的影响。DOX损害的LV功能显著降低了LV收缩压和舒张压、LV压力上升/下降速率、射血分数、缩短分数和收缩性指数。DOX导致心肌细胞结构改变。Phen治疗降低了DOX诱导的毒性，显著改善了心室功能，并减轻了心肌结构改变。Phen也不干扰DOX的抗肿瘤作用。结果证实了Phen对DOX诱导的心肌病具有心脏保护作用，且不消除DOX的抗肿瘤作用。
