Dobrić S, Dragojević-Simić V, Bokonjić D, Milovanović S, Marincić D, Jović P
National Poison Control Center, Military Medical Academy, Belgrade, Yugoslavia.
J Environ Pathol Toxicol Oncol. 1998;17(3-4):291-9.
It is known that the antineoplastic drug adriamycin (ADR) can cause cardiotoxic effects. Some data imply that pretreatment with selenium (Se) and the radio- and chemoprotector, amifostine (WR-2721), may confer a protective effect. The aim of this study was to evaluate the efficacy of single doses of Se and WR-2721, alone or in combination, in the prevention of acute ADR-induced cardiotoxicity in male Wistar rats. Se, in the form of sodium selenite (1.6 mg/kg i.p.), and WR-2721 (300 mg/kg i.p.) were given 24 hours and 20 minutes, respectively, before ADR (6 mg/kg i.v.). The cardiotoxicity of ADR was recorded 48 hours after its administration because earlier studies revealed that structural damage of the myocardium occurs within this period. Evaluation of these toxic effects, as well as of the cardioprotective efficacy of the administered drugs, was performed using (1) ECG-records before and during the infusion of the proarrhythmogenic compound, aconitine (8 microg/kg/min i.v.) and (2) the serum activity of creatine kinase (CK), aspartate aminotransferase-(AST), lactate dehydrogenase (LDH), and its isoenzyme alpha-hydroxybutyrate dehydrogenase (alpha-HBDH). The results showed that the arrhythmogenic dose of aconitine was significantly reduced in ADR-treated rats (57.22 vs. 99.65 microg/kg in control; p < 0.05) and that this proarrhythmogenic compound caused a significant increase in heart rate in such animals compared to controls. Pretreatment with Se, WR-2721, and their combination partly reversed the arrhythmogenic dose of aconitine to control (72.09, 82.1, and 88.99 microg/kg, respectively). Se failed to prevent an aconitine-induced increase in heart rate, whereas WR-2721 and their combination successfully counteracted this effect. In addition, ADR produced a significant increase in the serum activity of all monitored enzymes. Pretreatment with Se failed to prevent this increase, whereas pretreatment with WR-2721 did. The best result was obtained with their combination. We conclude that the radio- and chemoprotector, WR-2721, particularly in combination with Se, may provide a significant protective effect against acute ADR-induced cardiotoxicity in rats.
已知抗肿瘤药物阿霉素（ADR）可引起心脏毒性作用。一些数据表明，用硒（Se）以及放射和化学保护剂氨磷汀（WR - 2721）进行预处理可能具有保护作用。本研究的目的是评估单剂量的Se和WR - 2721单独或联合使用对预防雄性Wistar大鼠急性ADR诱导的心脏毒性的效果。分别在给予ADR（6 mg/kg静脉注射）前24小时和20分钟给予亚硒酸钠形式的Se（1.6 mg/kg腹腔注射）和WR - 2721（300 mg/kg腹腔注射）。在ADR给药后48小时记录其心脏毒性，因为早期研究表明在此期间会发生心肌结构损伤。使用（1）在输注致心律失常化合物乌头碱（8μg/kg/min静脉注射）之前和期间的心电图记录，以及（2）肌酸激酶（CK）、天冬氨酸转氨酶（AST）、乳酸脱氢酶（LDH）及其同工酶α - 羟丁酸脱氢酶（α - HBDH）的血清活性来评估这些毒性作用以及所给药的心脏保护药物的疗效。结果表明，在ADR处理的大鼠中，乌头碱的致心律失常剂量显著降低（对照组为99.65μg/kg，处理组为57.22μg/kg；p < 0.??5），并且与对照组相比，这种致心律失常化合物使此类动物的心率显著增加。用Se、WR - 2721及其组合进行预处理可使乌头碱的致心律失常剂量部分恢复至对照水平（分别为72.09、82.1和88.99μg/kg）。Se未能预防乌头碱引起的心率增加，而WR - 2721及其组合成功抵消了这种作用。此外，ADR使所有监测酶的血清活性显著增加。用Se预处理未能预防这种增加，而用WR - 2721预处理则可以。它们的组合获得了最佳结果。我们得出结论，放射和化学保护剂WR - 2721，特别是与Se联合使用时，可能对大鼠急性ADR诱导的心脏毒性提供显著的保护作用。
