Introduction

Animal models of human disease are used to investigate, describe, explain, and predict biological phenomena and drug effects. In vitro studies provide important information on the potency and spectrum of activity of new compounds by focusing on their interaction with molecular targets in cell-free, cellular, or tissue-based systems. However, in vivo testing exposes compounds to a variety of host factors and allows for potential interaction with other targets than those selectively tested in vitro. Thus it may not be surprising that many agents active in vitro are inactive or deviant from expectations in vivo. Animal

From: Cancer Drug Discovery and Development: Protein Tyrosine Kinases: From Inhibitors to Useful Drugs Edited by: D. Fabbro and F. McCormick © Humana Press Inc., Totowa, NJ

models have been extensively used in the preclinical testing of novel anticancer compounds (1-8), and they remain crucial for determining the safety of novel agents (9,10). In the space available it is impossible, and probably not desirable, to try to describe all the tumor models that have been used for testing kinase inhibitors. We will concentrate on some general principles that we have applied and illustrate some of the points by specific examples. Many of these principles not only will apply to the testing of kinase inhibitors; they can equally be applied, after suitable adaptation, to testing of many anti-tumor agents. Indeed, the generalities rather than the specifics probably apply to the testing of agents for many diseases. The focus will be on the preclinical profiling of epidermal growth factor receptor (EGFR) inhibitors in animal models, many of which are in advanced clinical testing (for general reviews, see refs. 11-15). Specific reviews are available on the development of erlotinib (16,17) and gefitinib (18).

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