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• W2057805280 abstract "Following exposure to 9‐(2‐phosphonylmethoxyethyl)adenine (an inhibitor of the cellular DNA polymerases α, δ and ϵ), human erythroleukemia K562, human T‐lymphoid CEM and murine leukemia L1210 cells markedly accumulated in the S phase of the cell cycle. In contrast to DNA replication, RNA synthesis (transcription) and protein synthesis (mRNA translation) were not affected by 9‐(2‐phosphonylmethoxyethyl)adenine. The ribonucleoside triphosphate pools were slightly elevated, while the intracellular levels of all four deoxyribonucleoside triphosphates were 1.5–4‐fold increased in 9‐(2‐phosphonylmethoxyethyl)adenine‐treated K562, CEM and L1210 cells. The effect of 9‐(2‐phosphonylmethoxyethyl)adenine on de novo (thymidylate synthase‐mediated) and salvage (thymidine kinase‐mediated) dTTP synthesis was investigated using radiolabelled nucleoside precursors. The amount of thymidylate synthase‐derived dTTP in the acid soluble pool was 2–4‐fold higher in PMEA‐treated than in untreated K562 cells, which is in accord with the 3–4‐fold expansion of the global dTTP level in the presence of 9‐(2‐phosphonylmethoxyethyl)adenine. Strikingly, 2‐derived dTTP accumulated to a much higher extent (i.e. 16–40‐fold) in the soluble dTTP pool upon 9‐(2‐phosphonylmethoxyethyl)adenine treatment. In keeping with this finding, a markedly increased thymidine kinase activity could be demonstrated in extracts of 9‐(2‐phosphonylmethoxyethyl)adenine‐treated K562 cell cultures. Also, in the presence of 200 μM 9‐(2‐phosphonylmethoxyethyl)adenine, 14‐fold less thymidylate synthase‐derived but only 3‐fold less thymidine kinase‐derived dTTP was incorporated into the DNA of the K562 cells. These data show that thymidine incorporation may be inappropriate as a cell proliferation marker in the presence of DNA synthesis inhibitors such as 9‐(2‐phosphonylmethoxyethyl)adenine. Our findings indicate that 9‐(2‐phosphonylmethoxyethyl)adenine causes a peculiar pattern of (deoxy)ribonucleotide metabolism deregulation in drug‐treated tumor cells, as a result of the metabolic block imposed by the drug on the S phase of the cell cycle." @default.
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• W2057805280 title "Impact of 9-(2-phosphonylmethoxyethyl)adenine on (deoxy)ribonucleotide metabolism and nucleic acid synthesis in tumor cells" @default.
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• W2057805280 doi "https://doi.org/10.1016/s0014-5793(99)00104-0" @default.
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