Cellosaurus logo
expasy logo

Cellosaurus publication CLPUB00271

Publication number CLPUB00271
Authors Wallace R.E., Lindh D., Durr F.E.
Title Studies on the development of resistance to mitoxantrone in human colon carcinoma cells in vitro.
Citation Proc. Am. Assoc. Cancer Res. 23:767-767(1982)
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.
Cell lines CVCL_2760; WiDr
CVCL_2N03; WiDr/R