Intracellular metabolism and action of acyclic nucleoside phosphonates on DNA replication

Vladimir M. Pisarev, Suk Hee Lee, Michele C. Connelly, Arnold Fridland

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

9-(2-phosphonylmethoxyethyl)guanine (PMEG) is an acyclic nucleoside phosphonate derivative that has demonstrated significant anticancer activity in a number of in vitro and in vive animal model systems. In this study, we compared the cellular metabolism of PMEG and 9-(2- phosphonylmethoxyethyl)adenine (PMEA), a clinically active anti-HIV and antihepatitis agent, and the inhibitory activities of their putative active diphosphate derivatives, PMEGpp and PMEApp, respectively, toward human cellular DNA polymerases. PMEG was significantly more cytotoxic than PMEA against a panel of human leukemic cells. The diphosphate derivatives were the major metabolites formed in cells on both these agents, with PMEGpp reaching cellular concentration approximately 4-fold higher than that achieved for PMEApp. These differences in cellular accumulation of the diphosphate derivatives were not, however, sufficient to account for the 30-fold difference in cytotoxicity between the two analogs. PMEGpp was also at least a 7-fold more effective inhibitor of in vitro simian vacuolating virus 40 DNA replication system than that of PMEApp (IC50 = 4.6 μM). Studies with a defined primed DNA template showed that PMEGpp was a potent inhibitor of both human polymerases α and δ, two key enzymes involved in cellular DNA replication, whereas PMEApp inhibited these enzymes relatively poorly. From these studies, we can conclude that the factors that contribute to the enhanced antileukemic activity of PMEG derives both from its increased anabolic phosphorylation and the increased potency of the diphosphate derivative to target the cellular replicative DNA polymerases.

Original languageEnglish (US)
Pages (from-to)63-68
Number of pages6
JournalMolecular pharmacology
Volume52
Issue number1
DOIs
StatePublished - Jul 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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