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Medicine Branch, To gather further insight into the interaction between P-glycoprotein
(Pgp) and its substrates, 167 compounds were analyzed in multidrug
resistant human colon carcinoma cells. These compounds were selected
from the National Cancer Institute Drug Screen repository using
computer-generated correlations with known Pgp substrates and
antagonists. The compounds were prospectively defined as Pgp substrates
if cytotoxicity was increased 
4-fold by the addition of cyclosporin A
(CsA) and as Pgp antagonists if inhibition of efflux increased
rhodamine accumulation by 4-fold. Among the 84 agents that met either
criterion, 35 met only the criterion for substrates, 42 met only the
criterion for antagonists, and only seven met both criteria. Thus,
compounds interacting with Pgp form two distinct groups: one comprising
cytotoxic compounds that are transported and have poor or no
antagonistic activity and a second comprising compounds with
antagonistic activity and no evidence of significant transport.
Vinblastine accumulation and kinetic studies performed on a subset of
18 compounds similarly differentiated substrates and antagonists, but
inhibition of 3H-azidopine labeling and induction of ATPase
activity did not. These data support an emerging concept of Pgp in
which multiple regions instead of specific sites are involved in drug
transport.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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