Gene expression profiling for pharmaceutical safety assessment.
Toxicogenomics is the application of gene expression profiling technology to toxicology. This results in the generation of very large and complex gene expression data sets associated with the development of toxicities. It is widely assumed that this data can be deconvoluted to reveal novel insights into toxicological processes that are of value to the task of risk assessment. More specifically, it is hoped that toxicogenomics will aid in the prediction of the toxic potential and mechanisms of toxicity of novel chemical entities. On the basis of such promise, the pharmaceutical industry has invested heavily in this area, as the perceived rewards in terms of improved pipeline efficiency and safer drugs are immense. Consequently, a great deal of groundwork has been done over the past several years to establish working methods in toxicogenomics, both within industry and academia, demonstrating utility in proof-of-concept studies, generating the databases on which some approaches depend, and developing new data analysis tools. Despite such activity, there is little reported evidence to suggest that toxicogenomics is making a significant impact on the discovery and development of drugs. This may partly reflect the understandable reluctance of pharmaceutical industries to share information in a competitive environment. It may also partly reflect difficulties in bridging the gap between theory and practice, as is required to deliver real value to the industry. This review will assess the successes and shortcomings of toxicogenomics, and consider how it can be usefully applied to a drug discovery pipeline.
Huby
Russell
R
AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Russell.Huby@astrazeneca.com
Tugwood
Jonathan D
JD
D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D013678:Technology, Pharmaceutical / Q000191:economics / Q000379:methods / Q000592:standards