Development and possible clinical use of antagonists for PDGF and TGF-β

Abstract

Platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) are examples of signaling molecules which control the growth, survival motility and differentiation of cells. PDGF stimulates the growth mainly of connective tissue cells, whereas TGF-β inhibits the growth of most cell types. PDGF and TGF-β exert their cellular effects by vinding to receptors equipped with tyrosine and serine/threonine kinase activities, respectively. Both factors have important roles e.g. during the embryonal development and in wound healing. Overactivity of PDGF or PDGF receptors contributes to the development of certain diseases characterized by excessive cell growth including fibrotic disorders, atherosclerosis and malignancies. Overactivity of TGF-β also contributes to fibrotic conditions, since TGF-β promotes accumulation of extracellular matrix molecules. In cancer, TGF-β is initially a tumor suppressor due to its ability to inhibit cell growth, however, at later stages of tumor progression TGF-β has tumor promoting activity by enhancing the invasive properties of tumor cells and by suppressing the immune system and promoting angiogenesis. The involvement of PDGF in TGF-β in serious diseases makes clinically useful antagonists highly desirable. A low molecular weight receptor kinase inhibitor of the PDGF receptor kinase is now tested clinically, and TGF-β antagonists are under development. The present review discusses the development and possible clinical use of antagonsts for PDGF and TGF-β.