fluorocoxib-a and Urinary-Bladder-Neoplasms

Conventional cystoscopy can detect advanced stages of bladder cancer; however, it has limitations to detect bladder cancer at the early stages. Fluorocoxib A, a rhodamine-conjugated analog of indomethacin, is a novel fluorescent imaging agent that selectively targets cyclooxygenase-2 (COX-2)-expressing cancers.. In this study, we have used a carcinogen N-butyl-N-4-hydroxybutyl nitrosamine (BBN)-induced bladder cancer immunocompetent mouse B6D2F1 model that resembles human high-grade invasive urothelial carcinoma. We evaluated the ability of fluorocoxib A to detect the progression of carcinogen-induced bladder cancer in mice. Fluorocoxib A uptake by bladder tumors was detected ex vivo using IVIS optical imaging system and Cox-2 expression was confirmed by immunohistochemistry and western blotting analysis. After ex vivo imaging, the progression of bladder carcinogenesis from normal urothelium to hyperplasia, carcinoma-in-situ and carcinoma with increased Ki67 and decreased uroplakin-1A expression was confirmed by histology and immunohistochemistry analysis.. The specific uptake of fluorocoxib A correlated with increased Cox-2 expression in progressing bladder cancer. In conclusion, fluorocoxib A detected the progression of bladder carcinogenesis in a mouse model with selective uptake in Cox-2-expressing bladder hyperplasia, CIS and carcinoma by 4- and 8-fold, respectively, as compared to normal bladder urothelium, where no fluorocoxib A was detected.. Fluorocoxib A is a targeted optical imaging agent that could be applied for the detection of Cox-2 expressing human bladder cancer.

Topics: Animals; Carcinogenesis; Carcinogens; Cell Line, Tumor; Cyclooxygenase 2; Cystoscopy; Disease Models, Animal; Female; Humans; Immunohistochemistry; Indoles; Melanoma, Experimental; Mice; Neoplasm Grading; Optical Imaging; Rhodamines; Urinary Bladder Neoplasms

The enzyme COX-2 is induced at high levels in tumors but not in surrounding normal tissues, which makes it an attractive target for molecular imaging of cancer. We evaluated the ability of novel optical imaging agent, fluorocoxib A to detect urinary bladder canine transitional cell carcinomas (K9TCC). Here, we show that fluorocoxib A uptake overlapped with COX-2 expression in primary K9TCC cells in vitro. Using subcutaneously implanted primary K9TCC in athymic mice, we show specific uptake of fluorocoxib A by COX-2-expressing K9TCC xenograft tumors in vivo. Fluorocoxib A uptake by COX-2-expressing xenograft tumors was blocked by 70% (P < 0.005) when pretreated with the COX-2 selective inhibitor, celecoxib (10 mg/kg), 4 hours before intravenous administration of fluorocoxib A (1 mg/kg). Fluorocoxib A was taken up by COX-2-expressing tumors but not by COX-2-negative human UMUC-3 xenograft tumors. UMUC-3 xenograft tumors with no expression of COX-2 showed no uptake of fluorocoxib A. In addition, fluorocoxib A uptake was evaluated in five dogs diagnosed with TCC. Fluorocoxib A specifically detected COX-2-expressing K9TCC during cystoscopy in vivo but was not detected in normal urothelium. Taken together, our findings show that fluorocoxib A selectively bound to COX-2-expressing primary K9TCC cells in vitro, COX-2-expressing K9TCC xenografts tumors in nude mice, and heterogeneous canine TCC during cystoscopy in vivo. Spontaneous cancers in companion animals offer a unique translational model for evaluation of novel imaging and therapeutic agents using primary cancer cells in vitro and in heterogeneous cancers in vivo.

Topics: Animals; Apoptosis; Blotting, Western; Carcinoma, Transitional Cell; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cystoscopy; Dogs; Female; Fluorescent Antibody Technique; Forkhead Transcription Factors; Heterografts; Humans; Immunoenzyme Techniques; In Vitro Techniques; Indoles; Mice; Mice, Nude; Optical Imaging; Rhodamines; Tumor Cells, Cultured; Urinary Bladder Neoplasms