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Platelet factor-4 (PF-4) is an ELR-negative chemokine that exhibits antiangiogenesis properties. PF-4 inhibits endothelial cell proliferation and migration, angiogenesis in vitro and in vivo, and tumor growth. However, tumor cells are not directly inhibited by PF-4. To date, a cell surface receptor that would explain the biological effects mediated by PF-4 has not been identified. PF-4 is able to interact directly with angiogenesis growth factors such as fibroblast growth factors (FGFs) and vascular endothelial growth factors and inhibits their interaction with cell surface receptors. Furthermore, dimerization of fibroblast growth factors is abrogated by PF-4. Whether PF-4 plays a role as an endogenous angiogenesis regulator is at present not clear. Several PF-4 fragments and modified molecules have been made that exhibit antiangiogenesis properties. Among these is a C-terminal fragment that has a defined structure, retains all the antiangiogenesis properties of the parent molecule, inhibits growth factor receptor binding, associates with FGFs, and destabilizes their three-dimensional structure. The relevance of these observations for the treatment of malignant disease is discussed.