EXPRESSION OF AN MDR GENE IS ASSOCIATED WITH A NEW FORM OF RESISTANCETO DEXAMETHASONE-INDUCED APOPTOSIS

A variant, MS23, of murine thymoma W7 cells, previously selected for i ts resistance to low concentrations of dexamethasone, is cross-resista nt to unrelated drugs such as puromycin and colchicine. We report here that transcription of the mouse mdr1 gene is activated and P-glycopro tein is expressed in MS23 cells. Moreover, additional variants with in creased resistance to dexamethasone and other drugs can be isolated fr om MS23 by stepwise selections in dexamethasone and colchicine. In one such variant (S7CD-5), the mdr1 gene is amplified and the mdr protein overexpressed. These variants have classical mdr characteristics: the y accumulate reduced concentrations of drugs (including dexamethasone) , and both drug sensitivity and intracellular accumulation can be rest ored by verapamil. The variants are most resistant to glucocorticoids with both 11- and 17-hydroxyl groups. The results indicate that we hav e identified a new form of glucocorticoid resistance, one associated w ith expression of the mouse mdr1 P-glycoprotein.