3-deazauridine and Neoplasms

Cytotoxic effects of 3-deazaguanosine (3-DGUO) result from the inhibition of DNA synthesis and incorporation of the drug into DNA. Synergistic antiproliferative effects of a combination of 3-deazaguanosine and 2-beta-D-ribofuranosylthiazole-4-carboxamide, a potent inhibitor of inosine monophosphate dehydrogenase, was observed in human tumor cells. Inosine reversed the antiproliferative effects of the 3-deazaguanosine but not 2-beta-D-ribofuranosylthiazole-4-carboxamide. 3-Deazaguanosine monophosphate was shown to inhibit the activity of the de novo purine synthesis enzyme, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide transformylase. The data suggested a cytotoxic effect of 3-DGUO associated with the inhibition of de novo purine synthesis by drug nucleotides, an effect which may account for the synergistic action noted.

Topics: 3-Deazauridine; Antimetabolites, Antineoplastic; Cell Division; Cells, Cultured; Drug Synergism; Humans; Inosine; Neoplasms; Ribavirin

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 phase I trial of the uridine analog 3-deazauridine was undertaken in 44 adults with solid tumors. The drug was given as a 5-day continuous infusion repeated every 3-4 weeks. The dose-limiting toxic effect was granulocytopenia. Patients with prior nitrosourea therapy or extensive irradiation also had significant thrombocytopenia, and the lowest dose tested, 800 mg/m2/day, was excessive for this group. Mucositis was occasionally severe and was particularly marked in previously irradiated areas. Nausea was mild to moderate. There were isolated episodes of rash, headache, chest pain, and blurred vision. For patients without extensive prior therapy, the recommended dose is 1000 mg/m2/day. No complete or partial remissions were noted.

Topics: 3-Deazauridine; Adult; Aged; Agranulocytosis; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Parenteral; Leukocyte Count; Male; Middle Aged; Nausea; Neoplasms; Platelet Count; Thrombocytopenia; Uridine

A rapid high-pressure liquid chromatographic assay for the detection and quantitation of 3-deazauridine-5'-triphosphate (deazaUTP), the active metabolite of the anticancer drug 3-deazauridine (deazaUrd), in cell extracts is described. This procedure permits the simultaneous detection and quantitation of CTP, the cellular concentration of which is affected by treatment with deazaUrd. Human lymphoblastoid cells (line CCRF-CEM) treated with 100 nmols of deazaUrd/ml in culture accumulate deazaUTP to greater than 25 nmols/10(7) cells after 4 hours. The concentration of CTP in these cells decreased exponentially with a half-life of 1.1 hours. After these cells had been incubated with 100 nmols of deazaUrd/ml and were resuspended in drug-free medium, the intracellular deazaUTP concentration decreased exponentially with a half-life of 3.4 hours. This assay has been applied to clinical studies of deazaUrd; high cellular deazaUTP concentrations have been detected in brain tumor tissue after deazaUrd infusion.

Topics: 3-Deazauridine; Brain Neoplasms; Chromatography, High Pressure Liquid; Humans; In Vitro Techniques; Leukemia, Lymphoid; Male; Middle Aged; Neoplasms; Neoplasms, Experimental; Nucleotides; Time Factors; Uridine; Uridine Triphosphate

Clinical studies of resistance to cytosine arabinoside have not produced agreement as to the specific biochemical lesions responsible for altered sensitivity, although experimental and clinical work supports the concept that a decreased ability to generate ara-CTP must be the ultimate effect of this lesion. 3-deazauridine, an inhibitor of CTP synthetase, was found to enhance ara-CTP production in murine tumor cells, and in the present study, was shown to inhibit deamination of ara-C at both the nucleoside and nucleotide level. Enhanced ara-CTP formation was observed in cells lacking cytidine deaminase (L1 210 and HL60), indicating that 3-deazauridine inhibition of deoxycytidylate deaminase may be important in this drug interaction.

Topics: 3-Deazauridine; Animals; Cytarabine; Cytidine Deaminase; Drug Interactions; Drug Resistance; Humans; Mice; Neoplasms; Tetrahydrouridine