Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Click here to register for free online access

Click here to sign up for SAGE Journal Email Alerts today!

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Free Full Text Free
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Foster, W. R.
Right arrow Articles by Car, B. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Foster, W. R.
Right arrow Articles by Car, B. D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Invited Review

A Retrospective Analysis of Toxicogenomics in the Safety Assessment of Drug Candidates

William R. Foster, Shen-Jue Chen, Aiqing He, Amy Truong, Vasanthi Bhaskaran, David M. Nelson, Donna M. Dambach, Lois D. Lehman-McKeeman and Bruce D. Car

Bristol-Myers Squibb Company, Research and Development, Princeton, New Jersey 08543, USA

Correspondence: Address correspondence to: William Foster, Bristol-Myers Squibb Co. PRI, LVL F4801C, Route 206 & Province Line Road, Princeton, NJ 08543, USA. E-mail:william.foster{at}bms.com

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.

Key Words: Toxicogenomics • transcriptomics • drug safety • toxicology • microarray • biomarkers • safety biomarkers

Toxicologic Pathology, Vol. 35, No. 5, 621-635 (2007)
DOI: 10.1080/01926230701419063
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?