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Predicting potential safety issues of drug candidates earlier in the drug-discovery process helps to prevent costly late-stage failure. Although in recent years advances have been made in the development of in silico models for prediction of some toxicity endpoints (e.g., mutagenecity, skin sensitization, and hERG binding), these in silico models are still not sufficiently global to robustly predict the diversity of chemotypes and mechanisms. Thus, there continues to be an important need for high-throughput in vitro toxicity screens. In particular, cell-based reporter assays using gene-expression technologies continue to be a promising area for in vitro toxicity applications. In this chapter, we highlight the in vitro cellular stress approaches that are being used to predict potential toxicity early in the drug-discovery phase with the hope of reducing late-stage attrition and improving success rates. These assays are able to predict potential in vivo toxicity following relatively brief exposures using small amounts of test compound. The advantage of cell-based assays is their high sensitivity and rapid reaction times. However cell-based assays are limited in their capabilities as they are usually conducted in vitro and, therefore cannot predict interactions that may occur in vivo. Moreover, many responses are tissue-, species-, and time-specific and therefore a single in vitro reporter gene assay may not accurately predict the responses observed in vivo. Despite the pitfalls of in vitro assays, the advance of toxicogenomic technologies and understanding will continue to evolve allowing development of more sensitive and simpler reporter gene vectors; thereby increasing our ability to design improved predictive models for application of early toxicity determination.

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