Anti-tumor activity of the tumor-vascular-disrupting agent ASA404 (vadimezan) in endocrine tumor models
Constanze Hantel1, Roman Franzev1, Alexandra Ozimek2, Thomas Mussack2 & Felix Beuschlein1
Vascular disrupting agents (VDAs) differ from angiogenesis inhibitors by attacking established tumor blood vessels rather than preventing growth of new ones. We investigated effects of the tumor-VDA ASA404 against neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) and adrenocortical carcinoma (ACC) 24 h after treatment of BON and NCIh295 tumor bearing mice with ASA404 (A), paclitaxel (P) or the combined administration (A+P). A significant decrease in cell proliferation (Ki 67 index, %) was detectable for BON tumors after all treatments (A: 51.6±0.7, P: 55.2±0.8 and A+P: 47.9±0.6; each P<0.0001 versus controls 60.2±0.8), for NCIh295 tumors only after P treatment (A: 46.6±1.5, P=0.87; P: 43.4±1.4, P<0.05 and A+P: 45.8±0.9, P=0.4; versus controls 46.88±1). BON tumors treated with A or A+P exhibited extensive necrotic areas not apparent in the control or P groups. TUNEL and CD31 staining showed that A or A+P treatments resulted furthermore in a significant increase of apoptotic cells (%) in BON tumor (A: 28.8±2.7, A+P: 34.3±3.6; each P<0.0001 versus controls 9.2±1.3 and P: 10.1±1.5) and a significant loss of microvessels compared with controls and P treatment (A: 7.3±0.8, P=0.0003 and A+P: 5.42±0.4, P<0.0001 versus controls 11.5±0.64 and versus P: 12.6±1.1). Interestingly, no significant effects on tumor morphology, apoptosis or microvessel density were detectable in NCIh295 tumors. To evaluate the mechanisms which cause these differences we initiated further in vitro analyses. As TNFα-signaling is assumed to mediate parts of ASA 404 induced effects we investigated induction of apoptosis and detected a fourfold higher rate of apoptosis in BON cells after TNFα treatment compared with NCIh295 cells (basal: 100%±2; BON: 823.1%±34.5 versus NCIh295: 244.2%±12.4; P=0.007). Thus, while ASA404 (vadimezan) treatment holds promise in the treatment of GEP-NETs, the utilized tumor models might help to delineate molecular mechanisms involved in VDA induced anti-tumor activity.