Blockade of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation

The family of vascular endothelial growth factor (VEGF) proteins include po tent and specific mitogens for vascular endothelial cells that function in the regulation of angiogenesis. Inhibition of VEGF-induced angiogenesis, ei ther by neutralizing antibodies or a dominant-negative soluble receptor, bl ocks the growth of primary and metastatic experimental tumors. Here me repo rt that VEGF expression is induced in Lewis lung carcinomas (LLCs) both in vitro and in vivo after exposure to ionizing radiation (IR) and in human tu mor cell lines (Seg-1 esophageal adenocarcinoma, SQ20E squamous cell carcin oma, T98 and U87 glioblastomas, and U1 melanoma) in vitro, The biological s ignificance of IR-induced VEGF production is supported by our finding that treatment of tumor-bearing mice (LLC, Seg-1, SQ20B, and U87) with a neutral izing antibody to VEGF-165 before irradiation is associated dth a greater t han additive antitumor effect. In vitro, the addition of VEGF decreases IR- induced killing of human umbilical vein endothelial cells, and the anti-VEG F treatment potentiates IR-induced lethality of human umbilical vein endoth elial cells. Neither recombinant VEGF protein nor neutralizing antibody to VEGF affects the radiosensitivity of tumor cells. These findings support a model in which induction of VEGF by IR contributes to the protection of tum or blood vessels from radiation-mediated cytotoxicity and thereby to tumor radioresistance.