Neutralizing anti-vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo

BACKGROUND. Neovascularization mediated by growth factors produced by tumors is critical for the growth of tumors. Vascular endothelial growth factor (VEGF) is one such growth factor. A neutralizing anti-VEGF antibody (A4.6.1) was recently shown in vivo to inhibit tumor angiogenesis and growth of the human rhabdomyosarcoma cell line A673. The antibody profoundly changed the growth characteristics of the tumor line from a rapidly growing malignancy to a dormant microcolony. METHODS. In the present study, we evaluated the effects of A4.6.1 (100 μg twice weekly, i.p.) on growth and angiogenic activity of spheroids of the human prostatic cell line DU 145 (diameter 700 μm at implantation) implanted in dorsal skinfold chambers in nude mice (n = 11). An antibody of the same isotype (n = 5) or saline (n = 5) was used as control. Tumor cells were prelabeled with a fluorescent vital dye (CMTMR), which allowed measurement of size of the implanted tumor spheroids throughout a two week observation period. FITC-dextran was used for plasma enhancement to visualize angiogenic activity. RESULTS. Tumors of control animals induced a neo-vasculature with high vascular density (350 ± 12 cm^-1). In animals treated with the anti-VEGF antibody, there was complete inhibition of neovascularization of the micro tumors and complete inhibition of tumor growth after the initial prevascular angiogenesis independent growth phase. CONCLUSIONS. These results demonstrate that inhibition of the key regulatory paracrine growth factor for endothelial cells, VEGF, results in complete suppression of prostate cancer induced angiogenesis and prevents tumor growth beyond the initial prevascular growth phase.