Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:39935-49-4 (DAU)
 148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-Deazauridine (NSC 126849) is a structural analog of uridine that inhibits the biosynthesis of Cytidine-5'-Triphosphate by competitive inhibition of Cytidine Triphosphate synthetase which is considered to be the primary mode of action of this nucleoside analog. Despite a paucity of clinical attention given to this drug as a single agent, it has generated much enthusiasm as a biological response modulator because of its synergistic effect with a number of antitumor agents including Cytosine Arabinoside, 5-aza-2'-deoxycytidine, 5-azacytidine, thymidine and D-galactosamine, although only the cytosine arabinoside/3-Deazauridine combination has been explored clinically. In this paper, the current status of the drug and future perspectives will be discussed.
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PMID:3-Deazauridine (NSC 126849): an interesting modulator of biochemical response. 242 37

The inhibition of uridine utilization by 3-deazauridine, an inhibitor of uridine kinase, and by dipyridamole, an inhibitor of the facilitated transport of nucleosides was examined. 3-Deazauridine (500 mg/kg) markedly inhibited (greater than 70%) the formation of uracil nucleotides from uridine in liver, kidney, and L1210 tumor cells. The degree of inhibition is greatly reduced by 6 hr after administration of the drug. Dipyridamole (100 mg/kg) did not significantly reduce salvage of uridine by liver or kidney and produced only small, transient reductions in salvage by L1210 tumors. Dipyridamole pretreatment did not alter the rate of clearance of uridine from the plasma.
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PMID:The effect of 3-deazauridine and dipyridamole on uridine utilization by mice. 242 41

Pyrimidine nucleotide pools were investigated as determinants of the rate of phosphorylation of 1-beta-D-arabinofuranosylcytosine (ara-C) by Ehrlich ascites cells and cell extracts. Cells were preincubated for 2 h with 10 microM pyrazofurin, 10 mM glucosamine, 50 microM 3-deazauridine, or 1 mM uridine in order to alter the concentrations of pyrimidine nucleotides. Samples of the cell suspensions were taken for assay of adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), cytidine 5'-triphosphate, guanosine 5'-triphosphate, deoxycytidine 5'-triphosphate (dCTP), and deoxythymidine 5'-triphosphate; then 1 microM [3H]ara-C was added and its rate of intracellular uptake was measured for 30 min. 3-Deazauridine lowered dCTP and stimulated ara-C uptake; however, pyrazofurin and glucosamine were potent inhibitors of ara-C uptake although they also decreased dCTP levels. Uridine stimulated ara-C uptake despite an increase in dCTP. A crude cytoplasmic extract was prepared by a procedure which permitted results of ara-C kinase assays to be expressed as pmol per min per 10(6) cells as in the cellular uptake studies. When assayed in the presence of mixtures of ribo- and deoxyribonucleoside triphosphates at concentrations close to their cellular levels, ara-C kinase activity closely approximated the cellular uptake rate for the five incubation conditions. Deletion of cytidine 5'-, guanosine 5'-, or deoxythymidine 5'-triphosphate from the assay mixture had little effect, while deletion of dCTP increased kinase activity 9-fold. Elimination of ATP also did not alter kinase activity in the presence of the remaining five ribo- and deoxyribonucleoside triphosphates; however, deletion of UTP reduced activity to 22% of the rate with the control mixture. When ara-C kinase was assayed with only 3 mM ATP, dCTP was a very potent inhibitor (50% inhibition concentration = 0.4 microM). Inhibition was complete at 10 microM dCTP, a concentration below the intracellular dCTP level in control cells (25 microM). With 0.9 mM UTP, enzyme activity was 2-fold greater in the absence of dCTP and the dCTP was 15-fold less potent as an inhibitor (50% inhibition concentration = 6 microM). We conclude that the actual phosphate donor for the phosphorylation of 1 microM ara-C in Ehrlich cells is UTP and not ATP. These observations suggest that successful combination protocols aimed at stimulating ara-C uptake by means of a decrease in dCTP levels must simultaneously preserve or increase UTP pools.
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PMID:Role of uridine triphosphate in the phosphorylation of 1-beta-D-arabinofuranosylcytosine by Ehrlich ascites tumor cells. 302 15

The effect of high concentrations of exogenous dCyd on the growth inhibitory properties of several inhibitors of de novo pyrimidine biosynthesis (dThd, 3-DAU, PALA, PF) was examined in three cultured human leukemic cell lines (HL-60, K-562, KG-1), and a dCyd kinase-deficient, Ara-C-resistant variant (HL-60/Ara-C). In the presence of dCyd concentrations (10(-3) M), far exceeding normal human plasma levels (0.5 to 4.0 X 10(6) M), substantial but partial reversal of pyrimidine antagonist-mediated growth inhibition and restoration of intracellular dCTP levels was noted in all cell types except HL-60/Ara-C. When high concentrations of dCyd (10(-3) M) were combined with low levels of uridine or cytidine (10(-5) M), full restoration of growth was observed in sensitive cell lines. When exposed to supraphysiologic concentrations of dCyd, HL-60/Ara-C cells were more sensitive to the growth inhibitory effects of pyrimidine antagonists than parent HL-60 cells; this phenomenon was maximal at 10(-4) M dCyd and was not observed in the presence of dCyd concentrations of 10(-6) M or lower. These studies suggest that in the presence of low concentrations of uridine or cytidine, perturbations in intracellular dCTP pools may play a critical role in determining the in vitro antiproliferative response of human leukemic myeloid cells to diverse inhibitors of de novo pyrimidine biosynthesis. They also raise the possibility that modulation of exogenous dCyd concentrations may improve the therapeutic efficacy of pyrimidine antagonists toward certain salvage pathway-deficient, drug-resistant leukemic cells.
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PMID:Effect of deoxycytidine on the in vitro response of human leukemia cells to inhibitors of de novo pyrimidine biosynthesis. 358 16

3-Deazauridine, a synthetic analogue of uridine and a potential antitumor agent, was found to possess antiviral activity against a number of ribonucleic acid-containing animal viruses in mammalian cell culture. Inhibition of virus-induced cytopathogenic effects by 3-deazauridine was observed in cells infected with rhinovirus types 1A and 13, coxsackievirus type A21, and PR-8 influenza virus, but not in cells infected with poliovirus type 2 or echovirus type 12. The extracellular yield of progeny influenza virus was found to be significantly reduced in titer in 3-deazauridine-treated Madin-Darby canine kidney cell cultures at 12 to 24 hr after infection. Although the precise biochemical mechanism of action of this antimetabolite's antiviral activity is not known, the compound does not appear to exert a direct virucidal effect on the influenza virion itself.
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PMID:3-Deazauridine: inhibition of ribonucleic acid virus-induced cytopathogenic effects in vitro. 479 50

The transport of uridine and 3-deazauridine was compared in two lines of cultured human lymphoblastoid cells that differ in their sensitivity to 3-deazauridine apparently because of reduced uridine-cytidine kinase activity in the resistant line. The kinetic parameters (+/- S.E.) of uridine transport were similar in the two cell lines: Km, 0.23 +/- 0.02 and 0.25 +/- 0.07 mM; and Vmax, 35 +/- 2 and 57 +/- 10 pmol/microliter of cell water per sec, respectively, for 6410/MP (parental) and 6410/MP/DU (resistant) cells. 3-Deazauridine, while transported with similar kinetic characteristics in both cell lines, was not as good a substrate for the nucleoside transporter as was uridine, and its transport was dependent on pH. Kinetic parameters, determined using calculated concentrations of the undissociated form of 3-deazauridine (pKa, 6.5), were: Km, 0.52 +/- 0.01 and 0.51 +/- 0.03 mM; and Vmax, 28 +/- 0.5 and 24 +/- 0.9 pmol/microliter of cell water per sec, respectively, for 6410/MP and 6410/MP/DU cells. At pH 8, a condition in which 97% of 3-deazauridine molecules are ionized, rates of transport were almost zero. It is concluded that the undissociated form of 3-deazauridine is the substrate for the nucleoside transporter.
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PMID:Transport of uridine and 3-deazauridine in cultured human lymphoblastoid cells. 658 Sep 47

3-Deazauridine, a uridine analog, was administered to 36 patients with acute leukemia by both intermittent and continuous iv infusion at doses ranging from 400 to 6000 mg/m2/day x 5, repeated at 1--3-week intervals. There were no complete or partial responses but three patients showed hematologic improvement. Major toxic effects were myelosuppression, stomatitis, vomiting, diarrhea, and skin erythema. Daily doses greater than 3000 mg/m2 were associated with significantly increased toxicity, including three drug-related deaths. The recommended dose for future studies is 2500 mg/m2/day as a continuous 5-day infusion.
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PMID:Phase I--II study of 3-deazauridine in adults with acute leukemia. 723 73