Gene expression profiling for pharmaceutical toxicology screening.
Advances in medicinal chemistry and high-throughput pharmacological screening are creating a multitude of potential lead compounds. There is also heightened concern about drug-induced toxicity, which is all too often uncovered late in development or at the post marketing stage. Together, these factors have created a need for novel approaches to screen for toxicity. There have been technological advances that enable study of changes in the gene expression profile caused by toxic insults and important steps made toward unraveling target organ toxicity at the molecular level. Thus, gene expression profile-based screens hold the promise to revolutionize the way in which compounds are selected for development. For screens focused on specific mechanisms of toxicity, reporter gene systems have proven utility, albeit modest because of our limited knowledge of which genes are true surrogate markers for toxicity. For broader forecasts of toxicity, DNA microarrays hold great promise for delivering practical gene expression profile screens (GEPS). For this promise to be realized, however, a number of technological hurdles must be cleared: (i) cost; (ii) reproducibility; (iii) throughput; and (iv) data analysis. Of equal if not greater importance, issues relating to the test systems used, the requisite number of genes to be studied and the size and scope of the database upon which forecasts will be based must be addressed. At present, the proof-of-concept for GEPS for toxicity is in hand, and we are poised to realize the goal of creating practical GEPS for application in compound prioritization.
Bugelski
Peter J
PJ
Achentoul Associates, Achentoul West, 211 Essick Road, Pottstown, PA 19465-8904, USA. peterbugelski@snip.net
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D014116:Toxicology / Q000379:methods*