Zhang Pei, Li Wei, Chen Jiaqing, Li Ruiting, Zhang Zunjian, Huang Yin, Xu Fengguo
Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University , Nanjing 210009, P. R. China.
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University , Nanjing 210009, P. R. China.
J Proteome Res. 2017 Apr 7;16(4):1753-1762. doi: 10.1021/acs.jproteome.7b00014. Epub 2017 Mar 17.
Nephrotoxicity is the dose-limiting adverse effect of cisplatin with large individual differences. Up to now, little has been done on how to recognize and predict the individual differences in either preclinical or clinical research. In the present study, important postdose indicators were screened out first and integrated into a grouping factor, according to which rats were recognized as lowly or highly sensitive individuals. Then, mass-spectrometry-based untargeted metabolomics approach was performed to dissect the metabolic differences in predose serum of the two groups. Eventually, branched-chain amino acids (BCAAs) were found to be most significant with the lowest p value of Mann-Whitney U test and the highest area under receiving operating characteristic curve (AUC-ROC). The findings were further confirmed by absolute quantitation of BCAAs using liquid chromatography-tandem mass spectrometry. Binary logistic regression showed that in the discovery set absolute BCAA contents in rat predose serum could predict cisplatin nephrotoxicity with accuracy of 85%. This result was validated by another two independent external validation sets with accuracy of 81.8 and 78.8%, respectively. This study could provide new insight into cisplatin nephrotoxicity and may help expedite personalized medicine of cisplatin or other antitumor drugs in future clinical studies.
肾毒性是顺铂的剂量限制性不良反应，个体差异较大。到目前为止，在临床前或临床研究中，关于如何识别和预测个体差异的研究做得很少。在本研究中，首先筛选出重要的给药后指标并整合为一个分组因素，据此将大鼠识别为低敏或高敏个体。然后，采用基于质谱的非靶向代谢组学方法剖析两组给药前血清中的代谢差异。最终，发现支链氨基酸（BCAAs）最为显著，其Mann-Whitney U检验的p值最低，接受者操作特征曲线下面积（AUC-ROC）最高。使用液相色谱-串联质谱对BCAAs进行绝对定量进一步证实了这些发现。二元逻辑回归显示，在发现集中，大鼠给药前血清中BCAAs的绝对含量能够预测顺铂肾毒性，准确率为85%。这一结果在另外两个独立的外部验证集中得到验证，准确率分别为81.8%和78.8%。本研究可为顺铂肾毒性提供新的见解，并可能有助于在未来的临床研究中加快顺铂或其他抗肿瘤药物的个性化医疗。
