Abstract 3244: Combination of COX-2 inhibitor Celebrex with androgen deprivation synergistically inhibits tumor growth in a syngeneic mouse model of prostate cancer

Abstract

Abstract Prostate cancer (PC) is the most common solid tumor in men in the United States. Effective treatment options include surgery and radiation therapy for localized tumors, whereas advanced cancer is treated by androgen deprivation. Unfortunately, most patients with metastatic prostate cancer will eventually relapse into a hormone-independent cancer that is notoriously resistant to chemotherapy. Thus, more effective therapeutic strategies are needed to improve this outcome, which leads to about 30 000 deaths every year. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown efficacy for the prevention or the treatment of several human cancers. Among them, specific COX-2 inhibitors have received particular attention because COX-2 is overexpressed in many epithelial tumors, including prostate, and because a number of studies have shown that they slow the growth of colon, lung and breast tumor xenografts in mice. In addition, COX-2 inhibitors have potent antitumor activity in prostate cancer both in vitro and in vivo. Celebrex (Celecoxib), the only COX-2 inhibitor still approved for clinical use, is being evaluated in clinical trials for the treatment of localized or advanced prostate cancer. In this study, we observed that celebrex in combination with androgen deprivation inhibits tumor growth much more efficiently that either treatment alone. A syngeneic pseudo-orthotropic mouse model and Intravital Microscopy (IVM) were used to measure several parameters of tumor progression and study the effect of Celebrex combined with androgen deprivation. Androgen-dependent TRAMP-C2 mouse prostate cancer cells were co-implanted with prostate tissue into the dorsal skinfold chamber of syngeneic C57Bl/6 mice. Mice were subjected to surgical or hormonal castration, alone or in combination with Celebrex. Tumor growth, apoptosis, mitosis and angiogenesis were measured. We observed that Celebrex alone inhibited tumor growth with no evidence of apoptosis but most likely through growth arrest during mitosis. Interestingly, Celebrex alone had no effect on angiogenesis. Castration alone had a significant angiostatic effect but tumor growth was inhibited only by 20%. In contrast, the combination of castration and Celebrex inhibited tumor growth by 65% and resulted in both increased apoptosis and increased mitotic arrest. Conclusion: our study provides evidence that Celebrex treatment of prostate cancer-bearing mice results in a lower proliferative rate in tumors. In addition, Celebrex potentiates the effect of castration to inhibit tumor growth in vivo. We propose therefore that administration of Celebrex during androgen deprivation may be more efficient than androgen deprivation alone and warrants further study. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3244.