Vora J, Khaw B A, Narula J, Boroujerdi M
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
J Pharm Pharmacol. 1996 Sep;48(9):940-4. doi: 10.1111/j.2042-7158.1996.tb06007.x.
Adriamycin has a wide spectrum of antitumour activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from the generation of oxygen free radicals. The objective of the present study was to investigate the influence of the antioxidant, butylated hydroxyanisole co-therapy on the cardiotoxicity of adriamycin, in-vivo. The aqueous solubility of butylated hydroxyanisole was enhanced by inclusion complex formation with hydroxypropyl-beta-cyclodextrin. The extent of drug-induced myocardial damage in rats was assessed using intravenous 111In-labelled antimyosin Fab and chronological changes in serum creatine kinase levels. There was a dose-related increase in myocardial antimyosin uptake in rats, which reached a plateau at an adriamycin dose of 10 mg kg-1. The antimyosin uptake at this dose (% dose g-1 = 0.1942 +/- 0.0150, n = 8) was significantly reduced by co-administration of butylated hydroxyanisole with adriamycin (10 mg kg-1 of each) to 0.1462 +/- 0.0116 (n = 5, P < 0.05). Assessment of cardiotoxicity in the rats was also performed by measuring serial changes in serum creatine kinase levels. Increasing doses of adriamycin caused an increase in serum creatine kinase levels with peak values obtained between 2 and 8 h after dosing. These values decreased upon co-administration of butylated hydroxyanisole with adriamycin at 10 mg kg-1, each and 30 mg kg-1 each by 29 and 41%, respectively. On the other hand, butylated hydroxyanisole did not inhibit the tumouricidal activity of adriamycin as investigated in-vitro using the NMU rat mammary adenocarcinoma cell-line. The significant reduction in anthracycline cardiotoxicity by butylated hydroxyanisole coadministration may result from its scavenging action on adriamycin-mediated free-radical formation or its enhancement of activity of enzymes involved in the metabolism of adriamycin.
阿霉素具有广泛的抗肿瘤活性，其主要副作用是与剂量相关的心脏毒性。有人认为这种心脏毒性是由氧自由基的产生所致。本研究的目的是在体内研究抗氧化剂丁基羟基茴香醚联合治疗对阿霉素心脏毒性的影响。通过与羟丙基-β-环糊精形成包合物提高了丁基羟基茴香醚的水溶性。使用静脉注射111In标记的抗肌凝蛋白Fab和血清肌酸激酶水平的时间变化来评估大鼠药物诱导的心肌损伤程度。大鼠心肌抗肌凝蛋白摄取量呈剂量相关增加，在阿霉素剂量为10mg/kg-1时达到平台期。丁基羟基茴香醚与阿霉素（各10mg/kg-1）联合给药可使该剂量下的抗肌凝蛋白摄取量（%剂量g-1 = 0.1942±0.0150，n = 8）显著降低至0.1462±0.0116（n = 5，P < 0.05）。还通过测量血清肌酸激酶水平的系列变化来评估大鼠的心脏毒性。阿霉素剂量增加导致血清肌酸激酶水平升高，给药后2至8小时达到峰值。丁基羟基茴香醚与阿霉素各10mg/kg-1和各30mg/kg-1联合给药后，这些值分别降低了29%和41%。另一方面，如使用NMU大鼠乳腺腺癌细胞系进行的体外研究所表明，丁基羟基茴香醚并不抑制阿霉素的杀肿瘤活性。丁基羟基茴香醚联合给药显著降低蒽环类药物的心脏毒性，可能是由于其对阿霉素介导的自由基形成的清除作用或其增强了参与阿霉素代谢的酶的活性。
