Antitumor effect of FP3 in a patient-derived tumor tissue xenograft model of gastric carcinoma through an antiangiogenic mechanism.

FP3 (KH902/KH903) is a novel vascular endothelial growth factor (VEGF) blocker with antiangiogenic properties. Previous studies revealed that FP3, a humanized fusion protein that combines ligand binding elements from the extracellular domains of VEGF receptors 1 and 2 and the Fc portion of IgG1, has an inhibitory effect on the VEGF-mediated proliferation and migration of human umbilical vein endothelial cells, and VEGF-mediated vessel sprouting of rat aortic rings in vitro. Thus, FP3 was considered as a new promising agent in treating human choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD). FP3 also has an antitumor effect in a non-small cell lung cancer cell line (A549) xenograft model in nude mice. However, little is known of the direct effects of FP3 on tumor vessels. In this study, we investigated the effects of FP3 on blood vessels in a patient-derived tumor tissue (PDTT) xenograft model of gastric carcinoma, using large tumors with established vasculature. Treatment with FP3 caused robust and early changes in endothelial cells and pericytes of vessels in the PDTT xenograft model. Vascular density decreased and vascular sprouting was suppressed by treatment with FP3. Pericytes did not degenerate to the same extent as endothelial cells, and those on surviving tumor vessels achieved a more normal phenotype. Our results revealed that FP3 has a direct and rapid antiangiogenic effect on tumor vessels, which was achieved mainly via regression of tumor vasculature, inhibition of new and recurrent vessel growth, and normalization of existing tumor vasculature.