BIOCHEMICAL-CHARACTERIZATION OF RESISTANCE TO MITOXANTRONE AND ADRIAMYCIN IN CACO-2 HUMAN COLON ADENOCARCINOMA CELLS - A POSSIBLE ROLE FOR GLUTATHIONE S-TRANSFERASES

Cytotoxicity of Adriamycin on human colon adenocarcinoma cell lines wa s investigated. Concentrations of Adriamycin producing 50% inhibition were very similar in HT29, Sw480, Sw620, and Sw1116 cells, whereas Cac o-2 cells were relatively insensitive. As compared to the Sw1116 cell line, Caco-2 cells were also insensitive to mitoxantrone. Sensitivity to cisplatin, 5-fluorouracil, or ethacrynic acid was comparable in bot h cell lines. To find the mechanism for this mitoxantrone and Adriamyc in resistance, several potential Adriamycin-detoxifying systems were c haracterized and quantified in both Sw1116 and Caco-2 cells. No dramat ic differences in glutathione content and expression of both selenium dependent- and independent glutathione peroxidase, UDP-glucuronyltrans ferase, and cytochrome P-450 were found. However, highly significant d ifferences in glutathione S-transferase activity were present, the exp ression of both class-pi and class-alpha glutathione S-transferases be ing much higher in the Caco-2 cell line. In addition, a slightly highe r content of P-170 glycoprotein was present in the Caco-2 cells. These findings suggest that glutathione S-transferases, and to a lesser ext ent the P-170 glycoprotein, may be involved in mitoxantrone and Adriam ycin resistance of Caco-2 colon carcinoma cells.