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Inhibition of salvage synthesis of nucleic acid by adenosine 3',5'-cyclic decylphosphoramidate in mastocytoma P-815 cells.

Abstract
Constant exposure of mastocytoma P-815 cells to adenosine 3',5'-cyclic decylphosphoramidate (1), which is permeable to the cell membrane and resistant to the action of phosphodiesterase, caused a dose-dependent (1 to 50 microM) inhibition in the synthesis of DNA and cell proliferation. Pretreating the cells with compound 1 (20 microM, 4 h) caused considerable inhibition of the incorporation of [3H]thymidine ([3H]TdR) into [3H]deoxythymidine 5'-triphosphate ([3H]dTTP) and that of [14C]hypoxanthine into nucleic acid, but not the synthesis of [14C]dTTP from [U-14C]aspartate. These results indicate that compound 1 preferentially inhibits the salvage synthesis of intracellular nucleotides and nucleic acids. Thymidine kinase, a key enzyme in salvage synthesis of nucleotides, was almost undetectable in cells pretreated with compound 1 at 20 microM for 4 h or at 5 microM for 15 h. On the other hand, compound 1 activated partially purified cAMP-dependent protein kinase A from bovine heart. Judging from these observations, it is likely that compound 1 readily permeates the cell membrane, activates cAMP-dependent protein kinase, then inhibits the salvage synthesis of nucleotides and nucleic acids by inhibiting thymidine kinase, which results in the inhibition of cell growth.
AuthorsM Saito, A Nasu, S Kataoka, N Yamaji, A Ichikawa
JournalJournal of pharmacobio-dynamics (J Pharmacobiodyn) Vol. 15 Issue 10 Pg. 597-604 (Oct 1992) ISSN: 0386-846X [Print] Japan
PMID1337357 (Publication Type: Journal Article)
Chemical References
  • DNA, Neoplasm
  • Hypoxanthines
  • Nucleic Acids
  • Thymine Nucleotides
  • adenosine 3',5'-cyclic decylphosphoramidate
  • Aspartic Acid
  • Cyclic AMP
  • Protein Kinases
  • Thymidine Kinase
  • Phosphoric Diester Hydrolases
  • thymidine 5'-triphosphate
Topics
  • Animals
  • Aspartic Acid (metabolism)
  • Cattle
  • Cell Division (drug effects)
  • Cell Membrane Permeability (drug effects)
  • Cell Nucleus (drug effects, metabolism)
  • Cyclic AMP (analogs & derivatives, pharmacology)
  • DNA Repair (drug effects)
  • DNA, Neoplasm (biosynthesis)
  • Humans
  • Hydrolysis
  • Hypoxanthines (metabolism)
  • Mast-Cell Sarcoma (metabolism)
  • Myocardium (enzymology)
  • Nucleic Acids (biosynthesis)
  • Phosphoric Diester Hydrolases (metabolism)
  • Protein Kinases (metabolism)
  • Thymidine Kinase (metabolism)
  • Thymine Nucleotides (metabolism)
  • Tumor Cells, Cultured

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