Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites

Malignant ascites is a common complication of advanced intraabdominal neopl asms for which standard treatments are suboptimal. Evidence suggests that t umor-mediated angiogenesis and enhanced vascular permeability in the perito neal wall due to high levels of vascular endothelial growth factor play a f undamental role in the pathogenesis of malignant ascites. To explore the ad vantage of viral vector-mediated "targeted antiangiogenic therapy" in ascit es formation, we constructed and administered adenoviral vectors encoding s everal different antiangiogenic proteins (angiostatin, endostatin, platelet factor 4, and a fusion protein between angiostatin and endostatin) alone o r in combination intraperitoneally in mice with peritoneal carcinomatosis f rom breast cancer (TA3 cells) and ovarian cancer (SKOV-3 i.p. and ES-2 cell lines) to explore the potential of additive or synergistic activity. Our d ata demonstrated statistically significant downregulation of ascites format ion, tumor growth, vascularity, and prolongation of animal survival after i ntraperitoneal treatment with antiangiogenic adenoviral vectors in three di fferent ascites tumor models. Combined treatment proved to be more effectiv e than treatment with one vector alone. Reduced ascites formation was accom panied by decreased microvascular density in the peritoneal wall and increa sed apoptosis of tumor cells after administration of antiangiogenic vectors in vivo. Of interest was the observation that AdPF4 caused a significant d ecrease in the level of VEGF secreted by tumor cells both in vitro and in T A3 ascites tumor-bearing animals in vivo. These data suggest that adenovira l vector-mediated delivery of genes encoding antiangiogenic proteins may re present a potentially new treatment modality for malignant ascites.