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Vol. 54, Issue 5, 907-917, November 1998
Laboratory of Virology and Experimental Chemotherapy, Rega
Institute for Medical Research, Katholieke Universiteit Leuven, B-3000
Leuven, Belgium
We have investigated the molecular basis of the 100-fold resistance of
mutant human erythroleukemia K562/PMEA-1 cells to the antiproliferative
potential of 9-(2-phosphonylmethoxyethyl)adenine (PMEA). Upon exposure
to high PMEA concentrations, comparable intracellular PMEA levels were
initially observed in mutant K562/PMEA-1 and wild-type K562/0 cells,
indicating that PMEA influx was unaltered. However, after 4 hr of
exposure to 0.2 µM
[3H]bis(pivaloyloxymethyl)-PMEA [bis(POM)-PMEA], the
total intracellular level of unphosphorylated and mono- and
diphosphorylated PMEA was 2.8-fold lower in K562/PMEA-1 than in K562/0
cells. Increased PMEA secretion from K562/PMEA-1 cells (compared with
K562/0 cells) became more pronounced upon prolonged exposure to
bis(POM)-PMEA; after 24 hr, K562/PMEA-1 cells showed 65-fold lower
total intracellular PMEA levels than K562/0 cells and at 48 hr,
>400-fold less total PMEA was detected in K562/PMEA-1 cells. In
addition, PMEA phosphorylation was 25- to 50-fold less efficient in
K562/PMEA-1 than in K562/0 cells, pointing to an additional defect at
the level of the metabolism of PMEA. The PMEA efflux mechanism was
shown to be temperature- and azide-dependent, was markedly inhibited by
indomethacin, and did not recognize adenine nucleotides or the
phosphorylated metabolites of 3'-azido-3'-deoxythymidine. Also, over a
28-hr period, PMEA efflux was not affected by an inhibitor of RNA
synthesis (actinomycin D) or protein synthesis (cycloheximide). Our
studies revealed that resistance of K562/PMEA-1 cells to PMEA is the
combined result of a severely impaired PMEA phosphorylation on the one
hand, and an enhanced PMEA secretion by a highly specific,
indomethacin-sensitive efflux pump, different from the classical
P-glycoprotein- and multidrug resistance protein-mediated resistance
mechanisms, on the other hand.
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