COX-2 inhibitor exhibits anti-cancer effects in prostate cancer

Atlanta-Initial results with neoadjuvant celecoxib (Celebrex) strongly suggest that this may be a promising agent in the management of patients with early localized prostate cancer, British researchers reported at the American Society of Clinical Oncology annual meeting.

Celecoxib, a nonsteroidal anti-inflammatory drug in the cyclooxygenase-2 (COX-2) inhibitor class, showed a number of anti-cancer effects on prostate tumors in men scheduled for radical prostatectomy, said first author Prasanna Sooriakumaran, MBBS, PhD, a lecturer in the department of urology, Royal Surrey County Hospital, University of Surrey, United Kingdom.

"In this first randomized controlled trial of celecoxib in patients prior to radical prostatectomy, celecoxib appears to significantly decrease tumor cell proliferation via anti-angiogenesis, induction of tumor apoptosis, and hypoxia, compared to no drug," Dr. Sooriakumaran said.

Celecoxib has been shown to inhibit tumorigenesis in a number of in vitro and in vivo models, Dr. Sooriakumaran explained. Based on these earlier findings, he and his colleagues carried out a study to investigate the biological effects of celecoxib in prostate cancer using immunohistochemical markers and GEP from DNA microarray analysis.

Higher levels of apoptosis

A total of 45 patients with cT1-2 prostate cancer were randomized in a 2:1 fashion to celecoxib, 400 mg twice daily, or placebo for 4 weeks, prior to prostatectomy. Tumor immunohistochemistry was performed for cell proliferation (Ki67), angiogenesis (CD-31, VEGF, VEGF-R2), hypoxia (HIF-1), apoptosis (TUNEL), and COX-2. Scoring was performed blind, and a random 20% of the patients were validated blindly by an immunopathologist. Perioperative biopsies on 19 patients also were sent for DNA microarray analysis to identify differences in GEP between the two study groups.

There was "substantial" or "almost perfect" inter-observer agreement in immunoscoring for all stains, Dr. Sooriakumaran pointed out. Univariate analyses showed that the celecoxib-treated patients had lower levels of cell proliferation, hypoxia, and COX-2 expression, and higher levels of apoptosis than did the control patients. On multivariate analysis for the combined model of all strains, this difference was of borderline significance (p=.056).

Principal components analysis confirmed a difference between the two study groups. Overall, the effects are strongly suggestive of an anti-cancer function for celecoxib, the researchers said.

Gene expression profiling revealed that 78 genes were significantly differentially expressed between the celecoxib and control groups, Dr. Sooriakumaran noted. In the celecoxib group, the tumor suppressor gene p73 and genes associated with oxidative stress were significantly upregulated. Also, genes associated with cell adhesion were significantly downregulated, consistent with a reduction in metastatic potential.