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.
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Authors | M Saito, A Nasu, S Kataoka, N Yamaji, A Ichikawa |
Journal | Journal of pharmacobio-dynamics
(J Pharmacobiodyn)
Vol. 15
Issue 10
Pg. 597-604
(Oct 1992)
ISSN: 0386-846X [Print] Japan |
PMID | 1337357
(Publication Type: Journal Article)
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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
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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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