Effects of the Cyclooxygenase Inhibitor, Piroxicam, in Combination with Chemotherapy on Tumor Response, Apoptosis, and Angiogenesis in a Canine Model of Human Invasive Urinary Bladder Cancer1

The objectives of this study were: ( a ) to determine the antitumor activity and toxicity of a cyclooxygenase inhibitor (piroxicam) combined with cisplatin chemotherapy in dogs with naturally-occurring, invasive transitional cell carcinoma (TCC) of the urinary bladder; and ( b ) to determine the effects of this treatment on prostaglandin E2 concentration, tumor cell proliferation and apoptosis, and angiogenesis. Pet dogs with naturally-occurring invasive TCC underwent complete tumor staging before and after 10 weeks of piroxicam/cisplatin treatment. Prostaglandin E2 concentrations were determined by immunoassay in snap-frozen tumor tissues. Apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), proliferation (proliferating cell nuclear antigen), and microvessel density were determined in formalin-fixed tissues. Urine basic fibroblast growth factor and vascular endothelial cell growth factor concentrations were determined by immunoassay. Partial remission (≥50% reduction in tumor volume) was noted in 6 of 12 dogs treated with piroxicam/cisplatin. Renal toxicity was dose-limiting. Apoptotic index doubled with treatment in 11 of 12 dogs but was not associated with tumor response. Proliferative index decreased in five dogs, and tumor decreased in size in three of the five dogs. Change in urine basic fibroblast growth factor and vascular endothelial cell growth factor was associated with tumor response. microvessel density was not associated with tumor response. In conclusion, piroxicam/cisplatin had antitumor activity against canine TCC, a disease that closely mimics human invasive urinary bladder cancer. Strategies to prevent renal toxicity of this protocol are needed. Induction of tumor apoptosis and reduction in angiogenic factor concentrations were observed, but additional studies are needed to further define the mechanisms of the antitumor activity of piroxicam/cisplatin.