Disease relevance of Upp1

• We have reported the elevation of uridine phosphorylase (UPase) in many solid tumors and the presence of a variant phosphorolytic activity in breast cancer tissues (M. Liu et al., Cancer Res., 58: 5418-5424, 1998) [1].
• The UPase cDNA has been expressed as a fusion protein in Escherichia coli using the pMal-C2 vector [2].
• Uridine phosphorylase was purified 10,300-fold from tumors of the murine colorectal adenocarcinoma cell line, Colon-26 [3].
• Compounds 1 and 2 were found to be very potent inhibitors of uridine phosphorylase isolated from Sarcoma 180 cells, with a Ki value of 0.098 and 0.020 microM, respectively, and exhibited no apparent cytotoxicity against Sarcoma 180 host cells [4].
• In addition, the uridine phosphorylase was found to be abundant in sarcoma-180 solid tumor, leading to a significantly higher concentration of converted 5-fluorouracil in this tumor than in other normal tissues [5].

High impact information on Upp1

• Recent data indicate that some EWS-Ets target promoters, including the uridine phosphorylase (UPP) promoter, harbor tandem binding sites for Ets and AP-1 proteins [6].
• Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice [7].
• Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine [7].
• Considering the role of UPase in 5-FU metabolism and the elevated expression of this protein in cancer cells compared with paired normal tissues, additional investigation should be warranted to firmly establish the clinical role of UPase in the tumor selective activation of 5-FU and capecitabine [1].
• In this cellular model, we establish the critical role of UPase as an important anabolic enzyme in 5-fluorouracil (5-FU) activation and pyrimidine salvage pathway regulation [1].

Chemical compound and disease context of Upp1

• Furthermore, a subline of L1210 leukemia resistant to 5'-DFUR but not to 5-fluorouracil was found to lack the uridine phosphorylase [5].

Biological context of Upp1

• UPase expression is affected by the c-H-ras oncogene and various cytokines through unknown mechanisms [8].
• Furthermore, IFN regulatory factor 1, c/v-Myb, and p53 binding sites are present in the promoter region, indicating that UPase expression may be directly regulated by cytokines and oncogene products [8].
• Genomic structure, chromosomal mapping, and promoter region analysis of murine uridine phosphorylase gene [8].
• The UPase gene contains nine exons and eight introns, spanning a total of approximately 18.0 kb [8].
• These data indicate that UPase is a critical enzyme in the regulation of uridine homeostasis and pyrimidine nucleotide metabolism, and 5-fluorouracil activity [9].

Anatomical context of Upp1

• Uridine phosphorylase (-/-) murine embryonic stem cells clarify the key role of this enzyme in the regulation of the pyrimidine salvage pathway and in the activation of fluoropyrimidines [1].
• Through transient expression analysis of the 5'-flanking region of UPase gene, we have evaluated the promoter activity for a series of fragments with 5'- to 3'-deletion in murine breast cancer EMT-6 cells and immortalized murine fibroblast NIH 3T3 cells [10].

Associations of Upp1 with chemical compounds

• The IC(50) is increased almost 16-fold in the knockout cells compared with the wild type cells, demonstrating the role of UPase in catalyzing the conversion of 5'DFUR to 5-FU [1].
• Potentiation of 5-fluoro-2'-deoxyuridine antineoplastic activity by the uridine phosphorylase inhibitors benzylacyclouridine and benzyloxybenzylacyclouridine [11].
• Enhancement of 5-fluoro-2'-deoxyuridine antitumor efficacy by the uridine phosphorylase inhibitor 5-(benzyloxybenzyl)barbituric acid acyclonucleoside [12].
• The kinetic analysis demonstrated that the recombinant UPase preferentially uses uridine, 5-fluorouracil, and uracil as substrates, although lower levels of activity were observed with 2-deoxyuridine and thymidine [2].
• Our data also shows the effect of UPase on the cytotoxicity of 5'-deoxy-5-fluorouridine (5'DFUR), a 5-FU prodrug [1].

Other interactions of Upp1

• L-UrdPase encodes a previously uncharacterized protein with similarity to an intestine-specific uridine phosphorylase [13].
• The present studies show that UMP synthase has cooperative kinetics toward OMP, and that a substrate cycle involving orotate phosphoribosyltransferase, cytoplasmic nucleotidase, and uridine phosphorylase maintains the cyclic interconversion: orotate----OMP----orotidine----orotate, etc [14].
• Toxoplasma gondii appear to have a single non-specific uridine phosphorylase enzyme which can catalyze the reversible phosphorolysis of uridine, deoxyuridine and thymidine, and a single cytidine deaminase activity which can deaminate both cytidine and deoxycytidine [15].

Analytical, diagnostic and therapeutic context of Upp1

• To better understand the biological and pharmacological significance of these findings, we have developed an UPase gene knockout embryonic stem (ES) cell model by specific gene targeting techniques [1].
• The effect of co-administration of 5-(phenylselenenyl)acyclouridine (PSAU), a new uridine phosphorylase (UrdPase, EC 2.4.2.3) inhibitor, on the efficacy of 5-fluoro-2'-deoxyuridine (FdUrd) was tested against murine colon C26-10 tumor xenografts [16].
• Further evidence for this is seen in the sustained 5- to 15-fold increase in both tissue and plasma uridine concentrations after treatment with benzylacyclouridine, a potent uridine phosphorylase inhibitor [17].
• Inhibitors of UrdPase are reported to enhance the chemotherapeutic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ameliorate zidovudine-induced anemia in animal models [18].
• 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy [19].

References