Endocrine Abstracts

Recently, we investigated effects of the Tumor-VDA ASA404 in tumor models for neuroendocrine tumors of the gastroenteropancreatic system and adrenocortical carcinoma 24 hours after treatment of BON and NCIh295 tumor bearing mice with ASA404 (A), paclitaxel (P) or the combination (A+P). We detected for BON tumors extensive necrotic areas as well as a significant decrease in cell proliferation, increase of apoptotic cells and reduction of microvessels after A or A+P treatment while no comparable effects were detectable in NCIh295 tumors. As TNFα -signaling is assumed to mediate parts of A induced effects we thenceforth utilized these models with their different responsiveness for characterization regarding TNFα stimulation and signaling. We detected in both groups a significant increase of TNFα serum levels compared with controls (P<0.05), but no significant differences between both tumor entities upon A treatment (BON: 2818±999%; NCIh295: 1165±422%, P=0.18). However, intra-tumoral TNFα content was significantly increased for BON tumors after A treatment while no differences were detectable for NCIh295 (basal: 100%; BON: 1178±263%, P=0.007; NCIh295: 220±86%, P=0.23). In vitro we detected a TNFα dependent 4-fold higher induction of apoptosis (basal: 100%; BON: 823±35% vs. NCIh295: 244±12%; P=0.007) and increase in IKK beta activity for BON but not for NCIh295 cells (basal: 100%; BON: 140±4%. P<0.001; NCIh295: 108±5%; P=0.32). Basal TNF receptor 1 expression was not significantly different, but we detected high levels of Toll-like-receptor (TLR)-4 in the BON tumor model in vitro and in vivo while receptor expression appeared to be abrogated for NCIh295. TLRs are widely expressed in cytokine producing cells and TNF alpha is an important downstream mediator of TLR-4 signaling. Thus, ASA404 treatment holds promise in the treatment of GEP-NETs. Furthermore, the utilized tumor models might help to delineate resistance mechanisms involved in VDA induced anti-tumor activity.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.