Herman E H, el-Hage A, Ferrans V J
Division of Drug Biology, Food and Drug Administration, Washington, D.C. 20204.
Toxicol Appl Pharmacol. 1988 Jan;92(1):42-53. doi: 10.1016/0041-008x(88)90226-8.
Loss of body weight, cardiomyopathy, and nephropathy were the main toxic manifestations found when male spontaneously hypertensive rats (SHR) and genetically related Wistar-Kyoto (WKY) rats were given 1 mg/kg doxorubicin iv once a week for 12 weeks. Each of these alterations was more severe in SHR. The most profound effects on body weight were observed from the 7th to the 12th week of dosing. During this period the body weight of SHR declined to preinjection control levels. Weight loss also occurred in WKY given doxorubicin, but was not as profound. Pretreatment with 25 mg/kg ICRF-187 ip attenuated the doxorubicin-induced loss in body weight in both types of animals. The frequency and severity of cardiac and renal lesions were graded on a score of 0 to 4. Alterations were found in hearts of all SHR and four of five WKY given doxorubicin alone. Cytoplasmic vacuolization and myofibrillar loss were more severe in SHR (average score, 2.6) than in WKY (average score, 1.0). At the end of the study mean arterial pressure was also decreased in SHR which had received doxorubicin alone. Pretreatment with ICRF-187 significantly attenuated the severity of the lesions in both SHR (average score, 1.0) and WKY (average score, 0); mean arterial pressure was higher in SHR treated with ICRF-187 and doxorubicin than in saline-treated SHR. Renal alterations, including glomerular vacuolization and tubular dilatation, were found in both strains of rats (average scores, 4.0 in SHR and 3.0 in WKY). ICRF-187 also reduced the severity of renal lesions (average scores, 2.0 in SHR and 1.0 in WKY). Thus, although ICRF-187 significantly alters myocardial, renal, and body weight effects of doxorubicin in both strains of rats, these toxic effects are more severe in SHR than in WKY. SHR provide an useful animal model for the critical examination of agents with potential protective activity against doxorubicin-induced toxicity.
当雄性自发性高血压大鼠（SHR）和基因相关的Wistar-Kyoto（WKY）大鼠每周静脉注射1 mg/kg阿霉素，持续12周时，体重减轻、心肌病和肾病是主要的毒性表现。这些改变在SHR中更为严重。在给药的第7至12周观察到对体重的最显著影响。在此期间，SHR的体重降至注射前对照水平。给予阿霉素的WKY也出现体重减轻，但程度没有那么严重。腹腔注射25 mg/kg ICRF-187预处理减轻了两种动物阿霉素诱导的体重减轻。心脏和肾脏病变的频率和严重程度按0至4分进行分级。单独给予阿霉素的所有SHR和五只WKY中的四只心脏出现改变。SHR（平均得分2.6）的细胞质空泡化和肌原纤维丧失比WKY（平均得分1.0）更严重。在研究结束时，单独接受阿霉素的SHR的平均动脉压也降低了。用ICRF-187预处理显著减轻了SHR（平均得分1.0）和WKY（平均得分0）病变的严重程度；用ICRF-187和阿霉素治疗的SHR的平均动脉压高于用生理盐水治疗的SHR。两种品系的大鼠均出现肾脏改变，包括肾小球空泡化和肾小管扩张（SHR平均得分4.0，WKY平均得分3.0）。ICRF-187也降低了肾脏病变的严重程度（SHR平均得分2.0，WKY平均得分1.0）。因此，尽管ICRF-187显著改变了两种品系大鼠中阿霉素对心肌、肾脏和体重的影响，但这些毒性作用在SHR中比在WKY中更严重。SHR为严格检验具有潜在保护活性以对抗阿霉素诱导毒性的药物提供了一个有用的动物模型。
