Amanda Callens

Molecular Imaging of Cyclooxygenase-2 in Canine Transitional Cell Carcinomas In Vitro and In Vivo.

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. Cancer Prev Res; 6(5); 466–76. ©2013 AACR.

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model

Abstract. We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1  mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1  mg/kg showed a peak of fluorocoxib A (92±28  ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

Congenital Diseases of the Lower Urinary Tract

Congenital lower urinary tract diseases occur with variable frequency and may result in clinical signs of urinary incontinence, urinary obstruction, or urination through abnormal openings. This article discusses diagnosis of congenital diseases of the urinary bladder and urethra and describes treatment of these disorders.

Evaluation of three herbal compounds used for the management of lower urinary tract disease in healthy cats: a pilot study:

Objectives Lower urinary tract disease (LUTD) occurs commonly in cats, and idiopathic cystitis (FIC) and urolithiasis account for >80% of cases in cats <10 years of age. Although several strategies have been recommended, a common recommendation is to induce dilute urine resulting in more frequent urination and to dilute calculogenic constituents. In addition to conventional therapy using modified diets, traditional Chinese and Western herbs have been recommended, although only one – choreito – has published data available. We evaluated three commonly used herbal treatments recommended for use in cats with LUTD: San Ren Tang, Wei Ling Tang and Alisma. We hypothesized that these three Chinese herbal preparations would induce increased urine volume, decreased urine saturation for calcium oxalate and struvite, and differences in mineral and electrolyte excretions in healthy cats. Methods Six healthy spayed female adult cats were evaluated in a placebo-controlled, randomized, crossover design study. Cats were randomized to one of four treatments, including placebo, San Ren Tang, Wei Ling Tang or Alisma. Treatment was for 2 weeks each with a 1 week washout period between treatments. At the end of each treatment period, a 24 h urine sample was collected using modified litter boxes. Results Body weights were not different between treatments. No differences were found in 24 h urinary analyte excretions, urine volume, urine pH or urinary saturation for calcium oxalate or struvite between treatments. Conclusions and relevance The results of this study do not support the hypothesis; however, evaluation of longer-term and different dosage studies in cats with LUTD is warranted.