Heparin-Like Drugs with Antiangiogenic Activity

The process of angiogenesis consists in the sprouting of new blood vessels from existing ones. This is a natural process that occurs in the human body and is essential for organ growth and repair. In the embryonic stage, the blood vessels provide the necessary oxygen, nutrients and instructive trophic signals to promote organ morphogenesis (Coultas et al., 2005). After birth the angiogenic process only contributes to organ growth and during adulthood the angiogenic process only occurs in the placenta during the pregnancy and in the cycling ovary, while most blood vessels remain quiescent. However the angiogenic activity could be reactivate because endothelial cells retain their angiogenic activity in response to a physiological stimulus (wound healing and repair) (Alitalo et al., 2005). This angiogenic activity is also critical in the development of solid tumors and metastasis (Ferrara, 2004; Folkman, 1990). Generally, a solid tumor expands until 1-2 mm3 is reached. At this point vascularization is required in order to ensure a supply of nutrients, oxygen, growth factors and proteolytic enzymes to the tumor (Folkman, 1990). To activate the angiogenic activity of endothelial cells, the tumor switches to an angiogenic phenotype and recruits blood vessels from the surrounding tissue, developing a dense vasculature that provides nutrients to the cancerous tissue (Figure 1). Numerous proangiogenic proteins are involved in tumor angiogenesis. Two of the most important families of pro-angiogenic proteins are the vascular endothelial growth factors (VEGF) and the fibroblast growth factors (FGF) (Garcia-Fernandez et al., 2010c). Most of these GF isoforms (this is not the case of the smallest isoform of VEGF-A (V121), that does not present a heparin-binding domain) need to interact with heparan sulfate proteoglycans molecules (HSPG) in order to recognize their specific tyrosine kinase receptor on cell membrane and activate the angiogenic process. These cell surface molecules are low affinity receptors that do not transmit a biological response, but are essential for these growth factors to recognize their union site to the signaling receptor (FGFR or VEGFR). Therefore, disruption of the interaction of these growth factors (GF) with cell surface HSPG seems an evident target for angiogenesis (Folkman, 1971; Folkman, 1990; Folkman, 1995). HSPGs are heparin-like molecules that favor the pro-angiogenic proteins oligomerization (Figure 1), which is necessary for the interaction with the endothelial cells membrane