3-deazauridine and Leukemia

Mycophenolic acid, an inhibitor of the enzyme IMP dehydrogenase, antagonizes the CTP synthetase inhibitor 3-deazauridine in its anti-proliferative effects on MOLT-3 human T leukemia cells. No depletion of CTP occurred, and decreased amounts of 3-deazuridine-triphosphate were measured in cells incubated with mycophenolic acid and 3-deazuridine. Most probably, these phenomena are related to the increased amounts of PRPP observed, which can result in an increased pyrimidine biosynthesis de novo and, as a consequence, a decreased metabolism of 3-deazauridine via the salvage pathway.

Topics: 3-Deazauridine; Carbon-Nitrogen Ligases; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; IMP Dehydrogenase; Leukemia; Ligases; Mycophenolic Acid; Phosphoribosyl Pyrophosphate; Ribonucleotides; Tumor Cells, Cultured

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.

Topics: 3-Deazauridine; Acute Disease; Animals; Antineoplastic Agents; Azacitidine; Cytarabine; Decitabine; Drug Evaluation; Drug Synergism; Galactosamine; Humans; Kinetics; Leukemia; Neoplasms; Thymidine; Uridine

A rapid and simple procedure for liquid chromatographic analysis of plasma 3-deazauridine (3-DU), an antineoplastic agent, was developed. The plasma was extracted with methanolic silver acetate to remove interfering ultraviolet-absorbing materials and the 3-DU partially purified on a small anion exchange column prior to chromatography on a reverse-phase (C18) column. 2'-O-Methyl-3-deazauridine was used as an internal standard. The mobile phase was 0.1 M ammonium acetate, pH 4.0, containing 5% methanol. The 3-DU was identified by its retention time and its characteristic ultraviolet absorbance ratio (280/254 nm) of 3.0. This method was used to determine the plasma concentration of 3-DU in three patients with acute leukemia. The patients received a 36-h infusion of 3-DU at a rate of 5.0 mg/kg/h. The mean steady-state plasma concentration of 3-DU at the end of the infusion was 22.1 micrograms/ml (range, 13.6-42.8 micrograms/ml) and the mean elimination half-life was 109 min (range, 92-136 min). 2,4-Dihydroxypyridine, a potential metabolite of 3-DU, was not detected in any of the plasma samples of the patients receiving a 3-DU infusion.

Topics: 3-Deazauridine; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Humans; Kinetics; Leukemia; Pyridines; Uridine

Topics: 3-Deazauridine; Adolescent; Adult; Aged; Cell Cycle; Cytarabine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Metabolic Clearance Rate; Middle Aged; Uridine

Topics: 3-Deazauridine; Arabinofuranosylcytosine Triphosphate; Arabinonucleotides; Cells, Cultured; Chromatography, High Pressure Liquid; Cytarabine; Cytidine Triphosphate; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Uracil Nucleotides; Uridine; Uridine Triphosphate