Olson Lisa E, Bedja Djahida, Alvey Sara J, Cardounel A J, Gabrielson Kathleen L, Reeves Roger H
Johns Hopkins University School of Medicine, Department of Physiology, Baltimore, Maryland 21205, USA
Cancer Res. 2003 Oct 15;63(20):6602-6.
Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Carbonyl reductase (CBR) has been implicated in the development of doxorubicin-induced cardiotoxicity. To test whether a decrease in CBR levels was protective against doxorubicin toxicity, we created a null allele of the Cbr1 gene. Mice with one functional copy of the gene (Cbr1 +/-) were healthy and grossly normal despite having decreased levels of Cbr1 transcript and protein. Control and Cbr1 +/- mice were administered doxorubicin at 20 mg/kg i.p. Cbr1 +/- mice showed decreased circulating levels of the cardiotoxic metabolite, doxorubicinol, after administration. Within 2 weeks, 91% of wild-type mice were severely affected (n = 11) compared with 18% of Cbr1 +/- mice (n = 11). Echocardiography and histological analysis showed that Cbr1 +/- mice were protected from gross and cellular level pathologies associated with doxorubicin treatment. Demonstration that inhibition of carbonyl reductase blocks the toxic effects on the heart has important implications for improving the use of doxorubicin in chemotherapy.
阿霉素是一种高效的抗肿瘤药物，但它会产生急性心脏损伤和慢性充血性心力衰竭等严重副作用。羰基还原酶（CBR）与阿霉素诱导的心脏毒性的发生有关。为了测试CBR水平的降低是否能预防阿霉素毒性，我们创建了Cbr1基因的无效等位基因。尽管Cbr1转录本和蛋白质水平降低，但具有该基因一个功能拷贝（Cbr1+/-）的小鼠健康且外观正常。对对照小鼠和Cbr1+/-小鼠腹腔注射20mg/kg阿霉素。给药后，Cbr1+/-小鼠循环中的心脏毒性代谢产物阿霉素醇水平降低。两周内，91%的野生型小鼠受到严重影响（n=11），而Cbr1+/-小鼠为18%（n=11）。超声心动图和组织学分析表明，Cbr1+/-小鼠免受了与阿霉素治疗相关的大体和细胞水平病变的影响。证明抑制羰基还原酶可阻断对心脏的毒性作用，这对改善阿霉素在化疗中的应用具有重要意义。
