) Long term objectives are to synthesize and develop new antiangiogenic compounds. We have synthesized and continue to synthesize novel compounds, which inhibit vascular endothelial growth factor production by human cancer cells and, therefore, are potential inhibitors of tumor angiogenesis. These compounds are not cytotoxic to normal vascular endothelial cells (VECs) and, therefore, unlikely to cause systemic toxicity.
Specific aims of the project are to develop methods to specifically deliver the inhibitor of VEGF synthesis to cancer cells which aberrantly express tissue factor (TF) and test the efficacy against human cancer grown m nude mice. This will be accomplished by coupling the agent to an inhibitor of coagulation factor VIIa, which possesses five times higher affinity for TF than VIIa. We and others found that a malignant phenotype of cancer expresses an increased level of TF and VEGF. TF is a transmembrane receptor for VIIa and the VIIa inhibitor. We have recently demonstrated that the cytoplasmic serine residues of TF mediates a signal transduction pathway for VEGF synthesis in cancer cells. VIIa and VIIa inhibitors are equally internalized within cancer cells by ligand-receptor- mediated endocytosis. Biotin-conjugated VIIa inhibitor specifically binds TF on cancer cells. Therefore, our novel synthetic compounds (molecular weight of 300-400, similar to biotin) linked to VIIa inhibitor are likely to specifically bind to TF. We propose to couple the compounds to VIIa inhibitor and to develop chemical coupling methods which allow proteolytic dissociation of the linkage between the compound and VIIa inhibitor inside the cancer cell.
