543 Background: Apricoxib, a selective COX-2 inhibitor, is currently in phase II trials, but its anticancer mechanisms of action could be better defined. Apricoxib inhibits COX-2 enzymatic activity and suppresses production of PGE2 and VEGF at low nanomolar concentrations but also directly inhibits tumor cell proliferation and survival with 10-20μM potency. In this study we characterized the in vivo activity of apricoxib in xenograft models of lung, breast and colorectal carcinoma. Also, we examined the relationship between the PK, PD and antitumor activity and the effect of the drug on both tumor cell-autonomous functions and aspects of the tumor-host relationship in the HT29 model. Methods: Human tumor xenografts were grown in nude mice and apricoxib was given daily PO. Drug levels were quantified by LC-MS and VEGF levels by ELISA. Vessel density, apoptosis, proliferation and EMT were assessed by immunohistochemistry. Results: Apricoxib significantly retarded tumor growth in NSCLC models and also enhanced the efficacy of SOC drugs in breast and lung tumors. In the HT29 model, the drug was active at both doses tested. Drug concentrations in plasma and tumors peaked at 2-10 μM within an hour and decreased rapidly to submicromolar levels but concentrations persisted above the active concentration for inhibition of PGE2 production for >24h. This strongly indicates that apricoxib exerts its in vivo activity via blockade of COX-2-dependent PGE2 production. Plasma VEGF levels decreased to zero for 6h post-dose, but returned to baseline by 24h. CD31 and Endomucin staining revealed no drug effect on microvessel density, although the percentage of immature vessels was reduced, as determined by pericyte coverage/NG2 expression. Apoptosis was significantly increased by TUNEL in apricoxib-treated tumors. PCNA analysis revealed a decrease in proliferating cells. ECAD expression was significantly increased in treated animals, whereas ZEB1 expression was lower, suggesting that COX-2 activity also plays an important role in EMT. Conclusions: Apricoxib possesses antitumor activity as a single agent and in combination. In the HT29 model, apricoxib inhibits tumor proliferation and survival, normalizes tumor vasculature and reverses EMT. [Table: see text]
COX-2 silencing enhances tamoxifen antitumor activity in breast cancer in vivo and in vitro
