UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
Proteomics. 2010 Apr;10(8):1592-608. doi: 10.1002/pmic.200900608.
A serious bottleneck in the drug development pipeline is the inability of current pre-clinical toxicology evaluation methods to predict early on, and with good accuracy, that a drug candidate will have to be removed from development due to toxicology/safety issues. The InnoMed PredTox consortium attempted to address this issue by assessing the value of using molecular profiling techniques (proteomics, transcriptomics, and metabonomics), in combination with conventional toxicology measurements, on decision making earlier in pre-clinical safety evaluation. In this study, we report on the SELDI-TOF-MS proteomics component of the InnoMed PredTox project. In this large scale, multi-site, multi-compound study, tissue and plasma samples from 14-day in vivo rat experiments conducted for 16 hepato- and nephro-toxicants with known toxicology endpoints (including 14 proprietary compounds and 2 reference compounds) were analyzed by SELDI-TOF-MS. We have identified seven plasma proteins and four liver proteins which were shown to be modulated by treatment, and correlated with histopathological evaluations and can be considered potential biomarker candidates for the given toxicology endpoints. In addition, we report on the intra- and inter-site variations observed based on measurements from a reference sample, and steps that can be taken to minimize this variation.
药物研发管道中的一个严重瓶颈是，当前的临床前毒理学评估方法无法早期、准确地预测候选药物由于毒理学/安全性问题而不得不被淘汰。InnoMed PredTox 联盟试图通过评估使用分子谱技术（蛋白质组学、转录组学和代谢组学）结合传统毒理学测量值在临床前安全性评估的早期决策中的价值来解决这个问题。在这项研究中，我们报告了 InnoMed PredTox 项目的 SELDI-TOF-MS 蛋白质组学部分。在这项大规模、多地点、多化合物的研究中，对来自 16 种具有已知毒理学终点的肝毒性和肾毒性化合物（包括 14 种专有化合物和 2 种参考化合物）的 14 天体内大鼠实验的组织和血浆样本进行了 SELDI-TOF-MS 分析。我们已经鉴定出 7 种血浆蛋白和 4 种肝脏蛋白，它们的表达受到治疗的调节，并与组织病理学评估相关，可以被认为是给定毒理学终点的潜在生物标志物候选物。此外，我们还报告了基于参考样本测量值观察到的内部和站点间的变化，并介绍了可以采取哪些措施来最小化这种变化。
