Cheng Q, Sanborn C, Ferguson D, Blanco J G
Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA.
Genet Mol Res. 2012 Apr 27;11(2):1109-16. doi: 10.4238/2012.April.27.10.
The anticancer anthracyclines doxorubicin and daunorubicin are used to treat a variety of cancers in dogs. The therapeutic utility of anthracyclines is limited by cardiotoxicity in some cases. Synthesis of anthracycline alcohol metabolites by carbonyl reductase 1 (CBR1) is crucial for the pathogenesis of cardiotoxicity. We hypothesize that genetic polymorphisms in canine cbr1 contribute to the variable pharmacodynamics of anthracyclines in dogs. DNA sequence variants in canine cbr1 were investigated in DNA samples from dogs of seven breeds. Thirteen SNPs were detected in canine cbr1. A 10-bp deletion in the 5'-untranslated region (5'-UTR) was found in specimens from the Labrador Retriever, Beagle, Siberian Husky, and Boxer breeds. The 5'-UTR also included a polymorphic "hot spot" region immediately downstream of the 10-bp deletion. DNA sequence variants in the "hot spot region" ranged from 1 to 21 bp in length. Bioinformatics searches identified a cluster of three to six potential binding sites for the transcription factor Sp1 in the DNA segment containing both the "hot spot" region and the 10-bp deletion. This information provides a foundation to allow us to investigate whether DNA sequence variants in the 5'-UTR of canine cbr1 impact the pharmacodynamics of anticancer anthracyclines in dogs.
抗癌蒽环类药物阿霉素和柔红霉素被用于治疗犬类的多种癌症。在某些情况下，蒽环类药物的治疗效用受到心脏毒性的限制。羰基还原酶1（CBR1）合成蒽环醇代谢产物对于心脏毒性的发病机制至关重要。我们假设犬类cbr1基因多态性导致了蒽环类药物在犬体内药效动力学的差异。我们对七个犬种的DNA样本中犬类cbr1的DNA序列变异进行了研究。在犬类cbr1中检测到13个单核苷酸多态性（SNP）。在拉布拉多寻回犬、比格犬、西伯利亚哈士奇和拳师犬品种的样本中发现5'-非翻译区（5'-UTR）有一个10个碱基对的缺失。5'-UTR还包括一个位于10个碱基对缺失下游的多态性“热点”区域。“热点区域”的DNA序列变异长度在1至21个碱基对之间。生物信息学搜索在包含“热点”区域和10个碱基对缺失的DNA片段中识别出三到六个潜在的转录因子Sp1结合位点簇。这些信息为我们研究犬类cbr1的5'-UTR中的DNA序列变异是否会影响抗癌蒽环类药物在犬体内的药效动力学提供了基础。
