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首页> 外文期刊>Journal of biochemical and molecular toxicology >Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration.
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Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration.

机译：阿霉素/紫杉醇组合对大鼠的心脏毒性：给药顺序和时机的影响。

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The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrateitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment.
机译：与单独的DOX相比，阿霉素（DOX）/紫杉醇（PTX）组合的更高的心脏毒性发生率仍然是阻碍有效化学疗法治疗的主要障碍。我们研究了两种药物的给药顺序和时间间隔对组合心脏毒性严重程度的影响。将雄性Wistar大鼠分成七组。腹膜内（i.p.）每隔2天以5 mg x kg（-1）的单剂量腹膜内施用DOX，每周2次，总累积剂量为20 mg x kg（-1）。 PTX由i.p.每2天服用20 mg x kg（-1）的剂量。两种药物均可单独注射或顺序注射。在一种情况下，DOX在PTX之前提前30分钟和24小时，而在另一种情况下，PTX在DOX之前提前30分钟和24小时。在最后一次DOX给药后48小时，通过生化和组织病理学检查评估了心脏毒性。 DOX诱导的心脏毒性表现为异常的生化变化，包括血清肌酸磷酸激酶同工酶（CK-MB），乳酸脱氢酶（LDH），谷胱甘肽过氧化物酶（GSH-Px）和天冬氨酸转氨酶（AST）活性水平显着增加。经DOX处理的大鼠的心肌组织显示丙二醛（MDA）产量和总硝酸盐/亚硝酸盐（NOx）水平显着增加，同时消耗了“内源性抗氧化剂储备”，包括GSH含量和GSH-Px活性水平。与单独使用DOX产生的变化相比，PTX处理产生的生化参数发生了显着变化，其幅度较低。两种药物的组合都会导致DOX诱导的心脏毒性反应加重，而与两种药物之间的给药顺序和时间间隔无关。 DOX处理后30分钟和24小时施用PTX与相反的顺序相比，显示了联合诱导的心脏毒性的扩大。这种恶化表现为所测血清和心脏组织参数的变化更为明显。大鼠心脏心室的组织病理学检查显示，DOX治疗可引起心肌细胞溶解和心肌坏死。与单独使用DOX或相反给药顺序治疗的大鼠相比，DOX治疗后给药PTX显示出广泛的心肌坏死。此外，在DOX治疗后24小时接受PTX治疗的大鼠表现出联合诱导的心脏毒性的夸张。总之，PTX可能协同加重DOX引起的心脏毒性。对于在DOX治疗后24小时接受PTX治疗的大鼠而言，这种作用可能会更加明显。

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