Affiliation:
1. Bristol-Myers Squibb Company, Research and Development, Princeton, New Jersey 08543, USA
Abstract
Toxicogenomics is considered a valuable tool for reducing pharmaceutical candidate attrition by facilitating earlier identification, prediction and understanding of toxicities. A retrospective evaluation of 3 years of routine transcriptional profiling in non-clinical safety studies was undertaken to assess the utility of toxicogenomics in drug safety assessment. Based on the analysis of studies with 33 compounds, marked global transcriptional changes (>4% transcripts at p < 0.01) were shown to be a robust biomarker for dosages considered to be toxic. In general, there was an inconsistent correlation between transcription and histopathology, most likely due to differences in sensitivity to focal microscopic lesions, to secondary effects, and to events that precede structural tissue changes. For 60% of toxicities investigated with multiple time-point data, transcriptional changes were observed prior to changes in traditional study endpoints. Candidate transcriptional markers of pharmacologic effects were detected in 40% of targets profiled. Mechanistic classification of toxicity was obtained for 30% of targets. Furthermore, data comparison to compendia of transcriptional changes provided assessments of the specificity of transcriptional responses. Overall, our experience suggests that toxicogenomics has contributed to a greater understanding of mechanisms of toxicity and to reducing drug attrition by empiric analysis where safety assessment combines toxicogenomic and traditional evaluations.
Subject
Cell Biology,Toxicology,Molecular Biology,Pathology and Forensic Medicine
Cited by
70 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献