Inhibition of Salvage Synthesis of Nucleic Acid by Adenosine 3', 5'-Cyclic Decylphosphoramidate in Mastocytoma P-815 Cells

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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 50μM) inhibition in the synthesis of DNA and cell proliferation. Pretreating the cells with compound 1 (20μM, 4h) caused considerable inhibition of the incorporation of [^3H] thymidine ([^3H] TdR) into [^3H] deoxythymidine 5'-triphosphate ([^3H] dTTP) and that of [^<14>C] hypoxanthine into nucleic acid, but not the synthesis of [^<14>C] dTTP from [U-^<14>C] 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 μM for 4 h or at 5μM for 15h. 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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