Hematopoietic growth factors (HGFs) have long been implicated in the development and progression of malignancies. Their pleiotropic effect on cells of different tissues means that in principle they have the capacity to stimulate a wide variety of functions that can contribute to a malignant phenotype. Stimulation of cell proliferation can accelerate tumor cell growth and mass, whereas inhibition of apoptosis may give a malignant clone a distinct survival advantage over normal cells. Similarly, certain growth factors can influence angiogenesis, potentially regulating tumor neovascularization, and effects on adhesion phenomena may facilitate tumor-cell migration and metastases.

A role for HGFs in oncogenesis has received support from observations that abnormal production of HGFs, either in an autocrine or paracrine manner, can occur in certain malignancies such as leukemias. In addition, some HGF receptors normally expressed on the cell surface at very low levels are known to be overexpressed in certain solid tumors. This potential for excessive cell stimulation, whether it is from lig-and or receptor origin, has strengthened the concept that some HGFs and their

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

receptors participate in the oncogenic process. It is not surprising that significant efforts have been directed toward developing antagonists of growth factors.

In this review, we focus on antagonists of HGF that are being used clinically or are on the verge of entering clinical trials. We have taken a less strict view of what an antagonist is to encompass a variety of molecules that, although they may work at different levels on the ligand-receptor complex, all have as a common thread the inhibition of receptor-initiated signaling and cellular function. In the concluding section, current limitations with the use of HGF antagonists are discussed, as well as the potential and opportunities to improve their use in oncology.

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