ABSTRACT
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 E(2) 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 E(2) 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 (> or =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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Carcinoma, Transitional Cell/veterinary , Dog Diseases/drug therapy , Neovascularization, Pathologic/drug therapy , Urinary Bladder Neoplasms/veterinary , Animals , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Transitional Cell/blood supply , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/metabolism , Cell Division/drug effects , Cisplatin/administration & dosage , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/administration & dosage , Dinoprostone/metabolism , Disease Models, Animal , Dog Diseases/metabolism , Dogs , Endothelial Growth Factors/urine , Female , Fibroblast Growth Factor 2/urine , Immunoenzyme Techniques/veterinary , Intercellular Signaling Peptides and Proteins/urine , Isoenzymes/metabolism , Lymphokines/urine , Male , Neoplasm Invasiveness , Piroxicam/administration & dosage , Prostaglandin-Endoperoxide Synthases/biosynthesis , Prostaglandin-Endoperoxide Synthases/metabolism , Urinary Bladder Neoplasms/blood supply , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/metabolism , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
The mechanisms by which cyclooxygenase inhibitors exert antitumor effects are not completely defined but are postulated to involve antiangiogenic effects and induction of apoptosis. In this study, we determined the effects of the cox inhibitor, piroxicam, on tumor response, apoptotic index, proliferative index, cyclooxygenase-2 expression, prostaglandin E(2) concentration, tumor microvessel density, and urine basic fibroblast growth factor and vascular endothelial growth factor concentrations in pet dogs with naturally occurring invasive transitional cell carcinoma of the urinary bladder. Piroxicam caused reduction in tumor volume in 12 of 18 dogs, and this was strongly associated with induction of apoptosis (Fisher's exact test P < 0.015) and reduction in urine basic fibroblast growth factor concentration.
