Abstract
High-grade invasive transitional cell carcinoma (InvTCC) kills >14,000 people yearly in the United States, and better therapy is needed. Cyclooxygenase-2 (Cox-2) is overexpressed in bladder cancer. Cox inhibitors have caused remission of InvTCC in animal studies, and cancer regression was associated with doubling of the apoptotic index in the tumor. The purpose of this study was to determine the apoptosis-inducing effects of celecoxib (a Cox-2 inhibitor) in InvTCC in humans. Patients (minimum of 10 with paired tumor samples) with InvTCC who had elected to undergo cystectomy were enrolled. The main study end point was induction of apoptosis in tumor tissues. Patients received celecoxib (400 mg twice daily p.o. for a minimum of 14 days) between the time of diagnosis [transurethral resection of bladder tumor (TURBT)] and the time of cystectomy (standard frontline treatment for InvTCC). Terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay and immunohistochemistry were done on TURBT and cystectomy samples. Of 13 cases treated with celecoxib, no residual invasive cancer was identified in 3 patients at the time of cystectomy (post celecoxib). Of the 10 patients with residual cancer, 7 had induction of apoptosis in their tumor. Induction of apoptosis was less frequent (3 of 13 cases; P < 0.04) in control patients not receiving a Cox inhibitor. Expression of vascular endothelial growth factor in the tumor cells decreased more frequently (P < 0.026) in the treated patients as compared with nontreated control cases. The biological effects of celecoxib treatment (increased apoptosis) justify further study of the antitumor effects of Cox-2 inhibitors in InvTCC.