Coudray C, Boucher F, Hida H, Tirard V, de Leiris J, Favier A
a Laboratoire de Biochimie C, Groupe de Recherche sur les pathologies oxidatives (GREPO), Centre Hospitalier Régional de Grenoble , France.
b Laboratoire de Physiologie Cellulaire Cardiaque , URA CNRS 1287, Université Joseph Fourier , Grenoble Cedex , France.
Redox Rep. 1996 Oct;2(5):323-32. doi: 10.1080/13510002.1996.11747068.
Adriamycin (doxorubicin; ADR) is an antineoplastic drug used to treat various cancers; however, its chronic us is unfortunately accompanied by cardiotoxicity. Previous results suggested that a free radical mechanism may contribute to ADR toxicity. Because it is often reported that cancer patients are deficient in selenium (Se), we hypothesised that ADR toxicity might be reduced by antioxidant agents such as vitamin E and Se. ADR-induced cardiotoxicity was examined in rats maintained on a Se-supplemented diet. The animals were kept on either a standard (0.22 mg/kg) or a Se-supplemented (2.5 mg/kg) diet starting 4 weeks prior to the first ADR treatment. ADR, or its excipient, was administered intraperitoneally in six equal injections over a period of 3 weeks giving a cumulative dose of 15 mg/kg body weight. Blood was collected in the thoracic cavity and the heart was subjected to a sequence of perfusion/partial ischemia/reperfusion ex vivo. Se status, GPx activities, vitamins E and C and MDA contents were determined on RBC and cardiac homogenates. ADR-treated rats showed a significant decrease in RBC Se (-29%) and in RBC Se-GPx (-34%) compared to the placebo group, and a significant increase in RBC MDA content (+2000%). This latter increase was attenuated by the Se supplementation (+1600%). In parallel, RBC vitamin E decreased markedly in the ADR-treated group (-50%) and was totally restored by the Se supplementation. Cardiac biochemical analyses confirmed the blood results. The present data confirm that a free radical mechanism does contribute to ADR toxicity, and show the importance of balancing the Se levels in ADR-treated subjects to limit its harmful myocardial action. Adecrease in ADR toxicity with no concomitant decrease in its antineoplastic activity would be of considerable value by improving the therapeutic benefit of the drug.
阿霉素（多柔比星；ADR）是一种用于治疗多种癌症的抗肿瘤药物；然而，不幸的是，长期使用会伴有心脏毒性。先前的结果表明，自由基机制可能与ADR毒性有关。由于经常报道癌症患者缺硒（Se），我们推测抗氧化剂如维生素E和Se可能会降低ADR毒性。在喂食补充硒饮食的大鼠中检测ADR诱导的心脏毒性。从首次ADR治疗前4周开始，将动物饲养在标准（0.22mg/kg）或补充硒（2.5mg/kg）的饮食中。ADR或其赋形剂在3周内分六次腹腔注射给药，累积剂量为15mg/kg体重。在胸腔采集血液，并对心脏进行体外灌注/部分缺血/再灌注序列处理。测定红细胞和心脏匀浆中的硒状态、谷胱甘肽过氧化物酶（GPx）活性、维生素E和C以及丙二醛（MDA）含量。与安慰剂组相比，ADR治疗的大鼠红细胞硒（-29%）和红细胞硒-谷胱甘肽过氧化物酶（-34%）显著降低，红细胞MDA含量显著增加（+2000%）。补充硒可减轻后者的增加（+1600%）。同时，ADR治疗组红细胞维生素E显著降低（-50%），补充硒后完全恢复。心脏生化分析证实了血液检测结果。目前的数据证实自由基机制确实与ADR毒性有关，并表明在接受ADR治疗的受试者中平衡硒水平以限制其对心肌的有害作用的重要性。在不伴随其抗肿瘤活性降低的情况下降低ADR毒性，通过提高药物的治疗益处将具有相当大的价值。
