The clinical use of hematopoietic growth factors (HGFs) is built on nearly 20 years of in vitro studies followed by preclinical animal studies. These laboratory and animal studies, undertaken before first use in humans, provided the basis for expectations of what the biologic effects in humans would be.

Reflecting the available technologies, the initial animal studies primarily evaluated the in vivo effects of factor excess after administration of factors to various animal species and included transgenic models, particularly when the supply of factor itself was limiting or issues of chronic factor exposure were to be addressed. With the development of genetic technologies to disrupt genes in mice selectively, animal models of

From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

factor deficiency were developed in the 1990s. These models were particularly useful for defining the indispensable and physiologic roles of factors and their multicompo-nent receptors. Increasing sophistication of the technologies for transgenesis and targeted gene modification enabled generation of animal models with inducible and tissue-specific genetic modifications that included not only gene disruptions but also truncations, point mutations, and gene replacement. Animal models incorporating these latter changes were usually generated to test hypotheses regarding the role of specific lesions in gene function or disease pathogenesis. This range of approaches collectively contributes to the preclinical evaluation of new biologic agents or to the modeling of particular disease processes so that pathogenic mechanisms can be better understood and therapeutic strategies can be assessed.

This chapter presents a descriptive overview of animal models of perturbed amounts of HGF, with a particular emphasis on genetic models, and focuses on those factors in clinical use: erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-11. Since diseases are often acquired and not infrequently present somatic rather than germline genetic lesions, animal models with acquired rather than congenital perturbations of HGF concentrations and signaling are also described.

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