GENE KNOCKOUT AND TRANSGENIC TECHNOLOGIES IN RISK-ASSESSMENT - THE NEXT-GENERATION

Transgenic and knockout mice have been proposed as substitutes for one of the standard 2-yr rodent assays. The advantages of using genetical ly engineered mouse models is that fewer mice are needed, the time to develop disease is greatly reduced, and the mice are predisposed to de veloping cancer by virtue of gain or. loss of functions. The models cu rrently being used have yielded a large amount of data and have proved to be informative for risk assessment; however, they are still far fr om ideal. In fact, they inherently do not reflect the complexity of mu tation and carcinogenesis in humans. Recent advances in technology and the creation of new knockout mice may produce more useful and more se nsitive models. This review covers two recent advances in technology-i nducible and regulatable gene expression and targeted genetic modifica tions in the genome-that will allow us to make better models. I also d iscuss new gene deletion and transgenic mouse models and their potenti al impact on risk-assessment assays. These models are presented in the context of four basic components or events that occur in the multiste p process leading to cancer: maintenance of gene expression patterns, genome stability and DNA repair, cell-cell communication and signaling , and cell-cycle regulation. Finally, surrogate markers and utility in risk assessment are also discussed. This review is meant to stimulate further discussion in the field and to generate excitement about work ing toward the next generation of risk-assessment models. (C) 1997 Wil ey-Liss, Inc.