AG-013736, a novel VEGF receptor and PDGF receptor inhibitor with potent activity against human bladder carcinoma in vitro and in vivo.
13109 The receptors for vascular endothelial growth factor and platelet-derived growth factor (VEGFR-2 and PDGFR) play essential and complementary roles in angiogenesis, and combined inhibition of these receptors may therefore result in potent antitumor activity in vivo. Here we characterized the effects of a small molecule tyrosine kinase inhibitor AG-013736 (Pfizer) in HUVEC and human bladder cancer cells. Previously, AG-013736 was reported to inhibit VEGFRs with picomolar potency and PDGFRs with nanomolar activity. All of the cell lines examined displayed cell surface VEGFR-2 and PDGFR α and β expression as measured by flow cytometry. Low nanomolar concentrations of AG-013736 blocked the HUVEC cell proliferation with inhibition of VEGF receptor 2 and PDGF receptor phosphorylation. AG-013736 caused regression of established subcutaneous human bladder cancer xenografts, effects that were associated with inhibition of VEGFR-2 and PDGFR β phosphorylation but not EGFR phosphorylation and reduction in tumor microvessel densities (MVDs). Our results demonstrate that AG-013736 has substantial anti-angiogenesis activity in preclinical models of human bladder cancer, which warrants further exploration either alone or with the combination of other pre-clinical drugs in bladder cancer treatment. No significant financial relationships to disclose.