Disease relevance of NSC146604

• Uridine (1, 5, or 10 g/kg/day) rescued mice from the lethal toxicity of 5-fluorouridine, whereas dThd or dUrd was ineffective [1].
• Combination treatment of the adenocarcinoma cell line with interferon and halogenated pyrimidines, under 4-day continuous exposure conditions, revealed significant synergy for growth inhibition with gamma- much greater than alpha/beta-interferon and with 5-fluorodeoxyuridine greater than 5-fluorouracil much greater than 5-fluorouridine [2].
• The inhibition of ribosomal RNA synthesis and maturation in Novikoff hepatoma cells by 5-fluorouridine [3].
• The sensitivity of Ehrlich ascites tumor cells in CF-1 mice to 5'-dFUrd, as well as to 5-fluorouridine, was established [4].
• Five murine and human tumor cell lines (N1S1, Sarcoma 180, L1210, HL-60, and Mia-PaCa) were exposed in vitro for 24 h to cytostatic doses of FUra or 5-fluorouridine [5].

High impact information on NSC146604

• Uridine-cytidine kinase was less inhibited in the presence of lowered UTP and CTP, which are potent feedback inhibitors of the enzyme, and enabled an enhanced formation of phosphorylated derivatives of 5-fluorouridine (FUrd) [6].
• Treatment of HeLa cells with 5-fluoro-[3H]uracil leads to the incorporation into cellular RNA of 5-fluorocytidine to the extent of about 0.2% of the 5-fluorouridine incorporated [7].
• Thus, by inactivating dihydropyrimidine dehydrogenase, EU prolonged the half-life for 5-FU, almost completely eliminated its catabolism for 4-6 h, which led to an increased accumulation of 5-fluorouridine mono-, di-, and triphosphates in both normal and tumor tissues [8].
• To elucidate the molecular mechanism by which the potent anticancer drug, 5-fluorouracil (5-FUra), inhibits cell proliferation, the effect of its metabolite, 5-fluorouridine triphosphate, on transcription of rat rRNA gene and processing of pre-rRNA was investigated in S-100 extract from the mouse lymphosarcoma cells [9].
• The effect of polyinosinic X polycytidylic acid [poly(I) X poly(C)] on the cell lethality produced by 5-fluorouracil [FUra] and 5-fluorouridine [FUrd] was examined in human colon carcinoma cell line HT-29 [10].

Chemical compound and disease context of NSC146604

• The E. coli pseudouridine synthase RluA, on the other hand, forms a covalent complex and is inhibited stoichiometrically by RNA containing 5-fluorouridine [11].
• The chemotherapeutic action of 5-fluorouridine in rats and mice, carrying the AS-30D and the TA3 ascites tumor, respectively, is significantly improved by pretreatment with an amino sugar together with 6-azauridine [12].
• This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m2 per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m2) [13].
• Potentiation by dipyridamole of 5-fluorouridine antitumor activity against a rat adenocarcinoma in vivo [14].
• E. coli mutants lacking cytosine/cytidine deaminase activities are able to more than double the extent of 5-fluorocytidine incorporation into their transfer and ribosomal RNAs, replacing cytidine with no detectable 5-fluorouridine incorporation [15].

Biological context of NSC146604

• Random sequence mutagenesis and resistance to 5-fluorouridine in human thymidylate synthases [16].
• Bladder tissue pharmacokinetics and antitumor effect of intravesical 5-fluorouridine [17].
• Kinetics of hCNT2-mediated transport of 5-fluorouridine and uridine were similar (K(m) values, 43-46 microM) [18].
• Possible rationales for these activities are discussed in terms of 5-F-cCMP and the corresponding 5'-monophosphate as potential prodrugs and as sources, following enzymatic deamination, of cytotoxic 5-fluorouridine or its 5'-monophosphate [19].
• The structures and stabilities of three RNA duplexes that differed only in the position of 5-fluorouridine (FUrd) substitution were elucidated using NMR spectroscopy and UV hyperchromicity studies to determine if FUrd substitution altered the structure or stability of RNA duplexes that contained G-U base pairs [20].

Anatomical context of NSC146604

• The incorporation of 5-fluorouridine triphosphate into RNA was enhanced in intestinal mucosa and liver [21].
• The main FUra compound was intact FUra itself (90%), and 5-fluorouridine accounted for 1% of the total radioactivity in the ascitic fluid [22].
• 5-Fluorouracil (5-FUra), 5-deoxy-5-fluorouridine (5'dFUrd), and 5-fluorouridine were compared for their relative antitumor activity, their capacity to inhibit leukocyte exudation and macrophage (macrophage) killing of tumor cells in vivo and in vitro, and their ability to induce leukopenia and monocytopenia [23].
• To identify more potent but less toxic antiproliferative drugs, the authors studied cell attachment and proliferation of 5-FU metabolites: 5-fluorouridine (FUR), 5-fluorodeoxyuridine (FUdR), 5-fluorouridine-5'-monophosphate (FUMP), and 5-fluorodeoxyuridine-5'-monophosphate (FdUMP) on human Tenon's fibroblasts in vitro [24].
• When resting cells are stimulated to grow in the presence of 5-fluorouridine, mRNA accumulates normally during the first eight hours, though new ribosome formation is completely blocked by the drug [25].

Associations of NSC146604 with other chemical compounds

• The effect of pretreatment with the fluoropyrimidines 5-fluorouracil (FUra), 5-fluorouridine (FUrd), 5-fluoro-2'-deoxyuridine (FdUrd), and 5'-deoxy-5-fluorouridine (5'-dFUrd) on the intracellular metabolism and in vitro cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) was explored in L1210 cells [26].
• By growth rate experiments, these uridine-cytidine kinase-deficient cell lines have altered sensitivities to the toxic pyrimidine analogs, 6-azauridine, 5-fluorouracil, and 5-fluorouridine and thus have been useful in elucidating the biochemical determinants involved in the metabolism of these compounds [27].
• Pre-mRNA containing 5-fluorouridine was spliced accurately and efficiently in the nuclear extract from HeLa cells, whereas 5-chloro-, and 5-bromouridine containing transcripts were not spliced [28].
• Sixteen unselected patients with non-resectable hepatocellular carcinoma were treated in a phase I study with 261 cycles of D-galactosamine and 6-azauridine prior to 5-fluorouridine [29].
• Potassium oxonate (O(XO)) competitively inhibits pyrimidine phosphoribosyltransferase (EC 2.4.2.10), which converts 5-FU to 5-fluorouridine 5'-monophosphate (FUMP) in vitro [30].

Gene context of NSC146604

• A strain carrying the disrupted allele and a fui1 mutant exhibit the same phenotype as they do not grow on a medium containing uridine as the sole source of pyrimidines and as they are resistant to 10(-3) M 5-fluorouridine (5FUI), a toxic analog of uridine [31].
• It is suggested that FdUrd exerts its anticancer effects against colon C26-10 tumors mainly through the catabolism of FdUrd to FUra by UrdPase, which then could be anabolized to 5-fluorouridine 5'-monophosphate (FUMP) by OPRTase and ultimately to other toxic 5-fluorouridine nucleotides, hence inducing the observed FdUrd toxic effects [32].
• Inhibition of ribosomal RNA synthesis and processing by 5-fluorouridine or of general RNA synthesis by camptothecin, an inhibitor of topoisomerase I, does not affect the methylation pattern of core histones [33].
• The activities of FdUrd phosphorylase, 5'-fluorouridine kinase, 5-fluorouridine phosphorylase, 5-fluorouracil phosphoribosyltransferase, and thymidylate synthase were not significantly different in the sensitive and resistant cell lines [34].
• Competitive inhibitors of Psi synthases, 5-fluorouridine-containing (5-FU) wild-type and mutant U4 RNAs, were used to investigate formation of Psi in U4 RNA [35].

Analytical, diagnostic and therapeutic context of NSC146604

• Examination of nuclear rRNA and 4 S RNA synthesis by agarose gel electrophoresis following 2-hr and 24-hr exposure to 5-fluorouracil or 5-fluorouridine indicated that processing of rRNA was not impaired, rRNA synthesis was inhibited by 10--40%, and 4 S RNA synthesis was unaffected [36].
• Glaucoma filtration surgery in monkeys using 5-fluorouridine in polyanhydride disks [37].
• By use of a specific extraction procedure, 5-fluorouridine was then quantitatively determined by capillary gas-liquid chromatography with a nitrogen-selective detector [38].
• First clinical experiences with a selective chemotherapy of hepatocellular carcinoma with 5-fluorouridine in combination with other antipyrimidines [29].
• The concentrations of 5-fluorouracil, 5-fluoro-5,6-dihydrouracil, 5-fluorouridine and 5-fluoro-2'-deoxyuridine in plasma, liver, kidney, lung and heart of rabbits were determined by high-performance liquid chromatography (HPLC) after drug administration by two different routes [39].

References