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Departments of
Infectious Diseases (V.M.P., M.C.C., A.F.) and
Virology and Molecular Biology (S.-H.L.), St. Jude Children's Research
Hospital, Memphis, Tennessee 38105
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
vivo 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 
and 
, 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.
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