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The Journal of Biological Chemistry Jun 1979Cells resistant to pyrazofurin and 6-azauridine have been selected from a simian virus 40-transformed Syrian hamster line and from a Chinese hamster lung line. By... (Comparative Study)
Comparative Study
Cells resistant to pyrazofurin and 6-azauridine have been selected from a simian virus 40-transformed Syrian hamster line and from a Chinese hamster lung line. By increasing the concentrations of inhibitors in several steps, mutant cells from both lines have been obtained which resist high concentrations (1 to 5 mM) of the two inhibitors separately or together. Orotidine-5'-phosphate decarboxylase (EC 4.1.1.23), the sixth and last enzyme in UMP biosynthesis, is inhibited by the nucleoside monophosphates derived from pyrazofurin or 6-azauridine. The activity of this enzyme is increased in each resistant cell line tested. Furthermore, there is a parallel increase in each case in the activity of the fifth enzyme of the pathway, orotate phosphoribosyltransferase (EC 2.4.2.10), which is not inhibited by pyrazofurin or 6-azauridine monophosphates, and the amount of increase is up to 67 times the level found in wild type cells. In contrast, the activities of the first three enzymes of UMP biosynthesis remain essentially unchanged in the mutants. Resistant Chinese hamster cells remain sensitive to 5-fluorouridine; this indicates that uridine kinase, the enzyme necessary to convert 6-azauridine to the monophosphate, is still functional.
Topics: Amides; Animals; Antibiotics, Antineoplastic; Azauridine; Carboxy-Lyases; Cell Line; Cell Transformation, Viral; Cricetinae; Drug Resistance; Kidney; Mesocricetus; Mutation; Orotate Phosphoribosyltransferase; Orotidine-5'-Phosphate Decarboxylase; Pentosyltransferases; Pyrazoles; Ribonucleosides; Ribose; Simian virus 40
PubMed: 220255
DOI: No ID Found -
Oncology 1982The expression of plasminogen activator activity (PA) by L1210 leukemic ascitic cells, obtained from the peritoneum of BDF1 mice, increases in the terminal stages of the...
The expression of plasminogen activator activity (PA) by L1210 leukemic ascitic cells, obtained from the peritoneum of BDF1 mice, increases in the terminal stages of the disease. Treatment of mice carrying advance leukemia (day 6 following inoculation with 10(6) cells i.p.) with 6-azauridine (AzUR) results in prolonged survival (2-3 days) and also in increased expression of PA activity by the ascitic cell population. Similar treatment with pyrazofurin (PF), another inhibitor of orotidylate decarboxylase and of de novo pyrimidine synthesis, fails to produce either of these effects. Neither AzUR or PF, given at the early stage of tumor growth (day 3), extend the life span nor do they cause increase of the PA activity. Thus, the elevation in PA activity following treatment with AzUR is associated with the asymptotic stage of the disease and this phenomenon correlates positively with the life-prolonging effects of this drug. An analysis of the PA activity elicited by intact cells, secretions, and cellular digests suggests that most of the activity originates on the surface of the cells. The results indicate that the described in vivo effect of AzUR, but not that of PF, on late-stage leukemia, is mediated by the changes in the fibrinolytic potential of the tumor or host cells rather than through the inhibition of the de novo pyrimidine synthesis.
Topics: Amides; Animals; Azauridine; Female; Fibrinolysis; Leukemia L1210; Mice; Mice, Inbred Strains; Orotidine-5'-Phosphate Decarboxylase; Plasminogen Activators; Pyrazoles; Pyrimidines; Ribonucleosides; Ribose; Sarcoma 180; Time Factors
PubMed: 6174911
DOI: 10.1159/000225619 -
Physical Chemistry Chemical Physics :... May 2010Excited state characteristics of 6-azauridine (6AUd), which is known as a medicine against psoriasis and neoplastic, were investigated with laser plash photolysis,...
Excited state characteristics of 6-azauridine (6AUd), which is known as a medicine against psoriasis and neoplastic, were investigated with laser plash photolysis, time-resolved thermal lensing, and near IR single photon counting method. The triplet-triplet absorption spectrum of 6AUd was observed for the first time. The formation quantum yield of excited triplet 6AUd (Phi(ISC)) was estimated by acetone triplet sensitization and actinometry with benzophenone to be 1.00 +/- 0.07 (248 nm excitation) and 0.78 +/- 0.05 (308 nm excitation). This excitation wavelength effect could be explained by intersystem crossing (ISC) to the excited triplet manifolds occurring during the relaxation on the potential energy surface (PES) of the S(1)(npi*) state and be in competition with internal conversion to the S(0) state after the relaxation to the minimum of the S(1)(npi*) state. 6AUd had a lower Phi(ISC) value than 6-azauracil (6AU) with the 308 nm excitation (Phi(ISC) = 0.93 +/- 0.04 for 6AU). The nucleoside has more vibrational modes than 6AU, and therefore the ribose would accelerate intramolecular vibrational energy redistribution and the relaxation to the minimum of the PES of the S(1)(npi*) state. Sensitized singlet oxygen formation of 6AUd was also detected in the O(2)-saturated condition with quantum yields of 0.49 +/- 0.01 with the 248 nm excitation, indicating the high phototoxicity of 6AUd.
Topics: Azauridine; Molecular Conformation; Quantum Theory; Singlet Oxygen; Thermodynamics; Ultraviolet Rays
PubMed: 20445916
DOI: 10.1039/b921568a -
Biochemical Pharmacology Nov 1965
Topics: Animals; Antimetabolites; Avoidance Learning; Behavior, Animal; Central Nervous System; Mice; Movement; Nucleosides; Reflex
PubMed: 5867507
DOI: 10.1016/0006-2952(65)90006-7 -
Clinics in Haematology Oct 1976Megaloblastic anaemia is due to a derangement of DNA synthesis caused by insufficient supply of one or other of the four deoxyribonucleoside triphosphate (dNTP)...
Megaloblastic anaemia is due to a derangement of DNA synthesis caused by insufficient supply of one or other of the four deoxyribonucleoside triphosphate (dNTP) precursors of DNA synthesis or by direct inhibition of one or other DNA polymerase. Reduced supply of the pyrimidine deoxythymidine triphosphate (dTTP) may be caused by folate or vitamin B12 deficiencies or by the action of dihydrofolate reductase inhibitors (e.g. methotrexate, pyrimethamine or trimethoprim), all of which cause reduced supply of the coenzyme 5, 10 methylene tetrahydrofolate (pentaglutamate) needed for thymidylate synthetase. Reduced dTTP supply may also be caused by direct inhibition of thymidylate synthetase by 5-fluorouracil. Reduced supply of both purines, deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP), may be caused by hydroxyurea, 6-mercaptopurine (and probably by another purine antagonist azaserine), whilst reduced supply of both pyrimidine DNA precursors, dTTP and dCTP (deoxycytidine triphosphate) may be due to inherited orotic aciduria or to treatment with azauridine. Cytosine arabinoside directly inhibits DNA polymerase. DNA replication is a discontinuous process and a number of enzymes are concerned with different aspects of the process. The parental strands partly unwind and a large number of initiation points or origins are activated on both strands. A primer RNA is first synthesised using the parental strand of DNA as template. Fragments of new DNA are then synthesised on the parental DNA template, starting at the RNA primer, under the action of one or other DNA polymerase (probably gamma). The RNA primer is then removed and the gap left is filled by further DNA synthesis under the action of a different DNA polymerase (probably alpha). The fragments of new DNA are joined to give newly synthesised stretches of DNA (replicons) which are then liigated together to form bulk DNA of enormous molecular weight. It is suggested here that reduced supply of one or other of the four deoxyribonucleoside triphosphate (dNTP) during the 'S' phase of the cell cycle (due to vitamin B12 or folate deficiency, drug treatment or other congenital or acquired abnormality in synthesis of the dNTP) impairs the cell's ability to elongate newly initiated DNA fragments by preventing gap-filling, the polymerase needed for gap-filling requiring substantially greater concentrations of the deoxyribonucleoside triphosphates than the polymerase involved in chain initiation. Cytosine arabinoside, which also may cause megaloblastosis, may affect principally the synthesis of new DNA fragments. Since active protein synthesis is needed for the cell to enter the S phase and RNA synthesis is needed to prime new DNA synthesis, megaloblastic anaemia may be expected to occur only when DNA synthesis is inhibited but protein and RNA synthesis are relatively unimpaired...
Topics: Anemia, Megaloblastic; DNA; Folic Acid; Folic Acid Deficiency; Formiminoglutamic Acid; Glycine; Homocysteine; Humans; Methionine; Methylmalonyl-CoA Mutase; Nervous System Diseases; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 10122
DOI: No ID Found -
Medicina Et Pharmacologia... 1967
Topics: Animals; Anti-Inflammatory Agents; Antimetabolites; Body Weight; Carrageenan; DNA; Edema; Extremities; Granuloma; Hydroxyproline; Leukocyte Count; Male; Rats; Triazines
PubMed: 6071774
DOI: 10.1159/000136984 -
Toxicology and Applied Pharmacology Sep 1970
Comparative Study
Topics: Acetates; Animals; Antimetabolites; Body Weight; Diarrhea; Erythrocyte Count; Female; Hemorrhage; Leukocyte Count; Male; Rats; Swine; Triazines
PubMed: 5471567
DOI: 10.1016/0041-008x(70)90208-5 -
Biochemical Pharmacology Nov 1965
Topics: Animals; Antimetabolites; Cats; Dogs; Guinea Pigs; Ileum; Kidney; Liver; Mice; Nucleosides; Physiology, Comparative; Rabbits; Rats; Urine
PubMed: 5867508
DOI: 10.1016/0006-2952(65)90007-9 -
Cancer Research Jan 1989L1210 cells treated with 1 mM 6-azauridine (AzUrd) (concentration causing 50% inhibition of cell growth, 3 microM) continued to divide at a reduced rate for 72 h before...
L1210 cells treated with 1 mM 6-azauridine (AzUrd) (concentration causing 50% inhibition of cell growth, 3 microM) continued to divide at a reduced rate for 72 h before stopping. However, a 24-h treatment was lethal to 99% of the cells, as determined by colony formation. To investigate the mechanism for this delayed cytotoxicity, the metabolism of AzUrd was studied. Cells incubated with AzUrd contained a new 254 nm-absorbing component, not found in control cells. It appeared to be 6-azauridine-5'-triphosphate, since it was the only peak in the triphosphate region of the chromatogram which contained 3H after incubation of cells with [3H]AzUrd. Incorporation of [3H]AzUrd into the acid-insoluble fraction (nucleic acids) was also detected. A role for this incorporation in the mechanism of AzUrd cytotoxicity was strongly suggested by the observation that cordycepin (0.01 mM) partially protected cells from the lethality of AzUrd, presumably by preventing its incorporation into RNA. The previously known inhibition of pyrimidine de novo synthesis by AzUrd was confirmed by a decrease in the intracellular contents of UTP and CTP in AzUrd-treated cells. Therefore, we propose that the inhibition of pyrimidine de novo synthesis and the incorporation into nucleic acid(s) may act in concert to produce the cytotoxic effects of AzUrd.
Topics: Animals; Azauridine; Cell Survival; DNA, Neoplasm; Deoxyadenosines; Hydrogen-Ion Concentration; Leukemia L1210; Mice; Nucleotides; RNA, Neoplasm; Uracil Nucleotides; Uridine Triphosphate
PubMed: 2463073
DOI: No ID Found -
Cancer Research Mar 1963
Topics: Azauridine; Neoplasms; Nucleosides; Research
PubMed: 14023746
DOI: No ID Found