Uridine phosphorylase (UPase) and thymidine phosphorylase (TPase) play critical roles in the metabolism of pyrimidines and their analogs used in cancer chemotherapy. These enzymes catalyze the reversible conversion of uridine, deoxyuridine and thymidine to the corresponding free bases and ribose or deoxyribose-1-phosphate. Uridine phosphorylase activity, in particular, has been reported to be elevated in breast cancers, colorectal cancer, oral squamous carcinomas, melanoma tissue, and lung adenocarcinomas when compared with adjacent normal tissues. Recently, a novel pyrimidine phosphorylase has been identified, called UPase-2. In human tissues, UPase-2 is predominantly expressed in kidney tissue, while in mouse tissue it is predominately expressed in the liver. Our recent studies have indicated that the UPase-2 isoform is overexpressed in UPase-1 knockout mice we have recently developed. A 37kDa (predicted MW of UPase-2) protein is overrepresented in liver lysate of UPase-/- mice after western blot analysis using a uridine phosphorylase polyclonal antibody. Real time RT-PCR analysis using UPase-2 specific primers shows a 4-fold increase in liver UPase-2 expression in UPase-/- mice compared to wild type mice. We also observed an increase in the expression of this enzyme in kidney and brain tissues; however, the enzymatic activity was below the limit of detection. No detectable mRNA levels were observed in spleen, lung or heart tissues. Interestingly, UPase-2 mRNA expression in wild-type and UPase-/- liver tissue decreased to 32% and 8% respectively after mice were fed diets containing 0.5% fenofibrate for 15 hours, however, UPase-1 mRNA expression increased 3.8-fold in the livers of wild-type mice. Fenofibrate, a ligand for peroxisome proliferator-activated receptor alpha, is used to treat high cholesterol and triglyceride levels, calling into question the role of UPase in lipid metabolism. Both the physiological role of UPase-2 in nucleoside metabolism and the homeostatic regulation of UPase-1 and UPase-2 in liver are presently unclear. To address this question, we plan to study this newly developed animal model to characterize UPase-2 contribution to pyrimidine and fluoropyrimidine metabolism, and the regulatory mechanisms affecting its expression and function.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 52.