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The vascular endothelial growth factor receptor-2 (VEGFR-2) is a tyrosine kinase receptor involved in the growth and differentiation of endothelial cells that are implicated in tumor-associated angiogenesis. In this study, novel 1-aryl-3-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]ureas were synthesized and evaluated for the VEGFR-2 tyrosine kinase inhibition. Three of these compounds showed good VEGFR-2 inhibition presenting low IC50 values (150-199 nM) in enzymatic assays, showing also a significant proliferation inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) at low concentrations (0.5-1 μM), using the Bromodeoxyuridine (BrdU) assay, not affecting cell viability. The determination of the total and phosphorylated (active) VEGFR-2 was performed by western blot, and it was possible to conclude that the compounds significantly inhibit the phosphorylation of the receptor at 1 μM pointing to their antiproliferative mechanism of action in HUVECs. The molecular rationale for inhibiting the tyrosine kinase domain of VEGFR-2 was also performed and discussed using molecular docking studies. [ABSTRACT FROM AUTHOR]

Abstract: Immunohistochemical analysis of the expression of transforming growth factor α (TGF-α) and its receptor, epidermal growth factor receptor (EGFR), was performed in a series of 86 invasive carcinomas of the breast. TGF-α immunostaining was observed in the majority of the cases (72.1%), both in epithelial cells and in adjacent stromal cells. EGFR was also present in tumors (34.2%) and in the endothelial cells (46.1% of the cases) near the tumors. A significant association was observed between TGF-α expression and angiogenesis evaluated by immunohistochemistry using an antibody against factor VIII-related antigen. No association was observed between TGF-α expression and other clinicopathologic features. In contrast, EGFR expression in the tumor was associated with features of poor prognosis, such as tumor size, histologic grade, lymph node status, estrogen receptor content, p53 expression, sialyl-Tn expression, and age. The presence of EGFR in endothelial cells was correlated to young patient age. We also observed an association of EGFR in endothelial cells and angiogenesis in tumors with a size of less than 2 cm. Inversely, in larger tumors, angiogenesis was only associated with tumor TGF-α expression. These results indicate that endothelial EGFR may play a role in the early steps of breast cancer angiogenesis. [ABSTRACT FROM AUTHOR]