| Abstract |
Tumor cells acquire resistance to initially effective cytotoxic drugs by
changes in enzyme activity, alteration in drug transport, or reduced drug
retention. Efforts have been made to develop a drug-resistant cell line
and study the mechanism(s) of resistance to the anticancer agent,
mitoxantrone, 1,4-dihydroxy-5,8-bis[[24(2-hydroxyethyl) amino]ethyl]-
amino]-9,10-anthracenedione dihydro-chloride (NSC 301739). Resistance to
mitoxantrone was established in human colon carcinoma cells (strain WiDr)
by continuous exposure of cell cultures to increasing concentrations of
drug. After 20 culture passages in the presence of drug, (0.02->0.08
mcg/ml a population of cells (WiDr/R) emerged which was approximately
30-40X more resistant to the cytotoxic effect of mitoxantrone than the
parent (WiDr/S) line; cross resistance to adriamycin was demonstrated.
Resistance to mitoxantrone was stable, evident in WiDr/R cells after >42
cell generations following removal of drug from the culture medium.
Studies with 14C-labeled mitoxantrone revealed that drug uptake was slowed
in WiDr/R cells. Maximum uptake was achieved in 4-5 h in WiDr/S cells
compared to >24 h in WiDr/R cells, and the total amount of drug associated
with cellular DNA of WiDr/R cells was about one-half the amount of drug
associated with DNA of WiDr/S cells. Drug uptake by WiDr/R cells was
clearly enhanced by Tween 80. When incubated in drug-free medium following
drug exposure, WiDr/R cells retained 80% of the drug compared to 100%
retention by WiDr/S cells. These studies suggest that resistance to
mitoxantrone may be due to an alteration of the cell membrane and/or
cytoplasm, resulting in decreased uptake and impaired interaction of drug
with DNA.
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