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Vol. 290, Issue 2, 854-862, August 1999
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis,
Indiana
Overexpression of ATP-dependent drug efflux pumps, P-glycoprotein (Pgp)
or multidrug resistance-associated protein (MRP), confers multidrug
resistance to tumor cells. Modulators of multidrug resistance block the
action of these pumps, thereby sensitizing cells to oncolytics. A
potent Pgp modulator is LY335979, which fully sensitizes Pgp-expressing
cells at 0.1 µM in cytotoxicity assays and for which Pgp has an
affinity of 59 nM. The present study examines its effect on
MRP1-mediated drug resistance and cytochrome P-450 (CYP) activity and
its ability to serve as a Pgp substrate. Drug resistance was examined
with HL60/ADR and MRP1-transfected HeLa-T5 cells. Drug
cytotoxicity was unaffected by 1 µM LY335979; leukotriene C4 uptake
into HeLa-T5 membrane vesicles was unaffected. Because the substrate
specificity of Pgp and CYP3A overlap, the effect of LY335979 on the
1'-hydroxylation of midazolam by CYP3A in human liver microsomes was
examined. The apparent Ki was 3.8 µM,
~60-fold higher than the affinity of Pgp for LY335979. The
modulator's effect on Pgp was evaluated with Pgp-overexpressing
CEM/vinblastine (VLB)100 and parental CCRF-CEM
cells. Both cell lines accumulated [3H]LY335979 equally
well and did not efflux [3H]LY335979 during a 3-h
incubation, indicating that it is not a substrate of Pgp.
Equilibrium-binding studies with CEM/VLB100 plasma
membranes and [3H]LY335979 showed that Pgp had a
Kd of 73 nM, which is in good agreement with
the previously determined Ki value. Thus,
LY335979 is an extremely potent Pgp, and not MRP1 or MRP2, modulator
and has a significantly lower affinity for CYP3A than for Pgp.
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