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Uridine phosphorylase-2 (UPase-2) is a novel protein with pyrimidine nucleoside phosphorolytic activity recently cloned and characterized. Uridine phosphorylase (UPase-1) catalyzes the reversible phosphorolytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1-phosphate. The novel enzyme shows broader specificity compared to UPase-1. The enzyme catalyzes the phosphorolysis of the naturally occurring nucleosides under normal physiological conditions and is important in the activation and metabolism of several nucleoside analogs currently used in cancer chemotherapy. These include 5-flourouracil (5-FU) and its pro drugs 5-fluoro-2’-deoxy uridine (5-FdUrd) and 5’- deoxy-5-flourouridine which are used for the treatment of several solid malignancies. The identification and characterization of a novel uridine phosphorylase could be important for studies of both nucleoside metabolism as well as for studies on the pharmacological activation of therapeutic pyrimidine nucleoside analogs. Furthermore, the distribution of UPase-2 could help to elucidate the increased phosphorolytic activity that we have reported in breast and other solid tumors compared to adjacent normal tissue. In the study we have carried out, a similar 35.6KDa protein was produced for both human and mouse cDNA clones. UPase-2 was studied for substrate specificity where both human and murine enzymes showed similar specificity for uridine and thymidine in comparison to previous reports. We are in the process of further evaluating the kinetic differences between UPase-1 and UPase-2 to better understand the role of this novel phosphorolytic enzyme. The physiological function of UPase-2 in nucleoside metabolism and the reasons for a marked difference in tissue specific expression have yet to be clarified. As we and others have suggested, the manipulation of the uridine pools by combining cytotoxic nucleoside analogs with uridine and uridine phosphorylase inhibitors could lead to an improvement of the therapeutic index of pyrimidine nucleoside analogs. Thus, by further studying the differences in substrate specificity and distribution of UPase-1 and UPase-2 selective inhibitors of these enzymes may be designed to improve the therapeutic outcome of fluoropyrimidine-based chemotherapeutic regimens.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]