RAPID UP-REGULATION OF MDR1 EXPRESSION BY ANTHRACYCLINES IN A CLASSICAL MULTIDRUG-RESISTANT CELL-LINE

Studies were carried out in a Variant human multidrug-resistant (MDR) cell line CEM/A7R, which expresses very low Levels of mdr1 mRNA and P- glycoprotein (P-gp). The induction of mdr1 RNA expression by three ant hracyclines, (doxorubicin, daunorubicin, epirubicin), VP-16 and two vi nca alkaloids (vincristine, vinblastine) was semiquantitatively assess ed by scanning Northern blots on a phosphorimager. The relative level of mdr1 expression was expressed as ratio of mdr1 to the internal RNA (actin). A significant increase (P < 0.02) in expression of mdr1 was n oted within 4 hrs of exposure to 1.5 mu g ml(-1) daunorubicin or epiru bicin. Neither vinblastine nor vincristine had any effect on mdr1 leve ls after an 8 h exposure. With increasing concentrations of daunorubic in or epirubicin in a fixed 24 h time period, mdr1 expression increase d, although a biphasic response was seen. Based on MRK 16 binding, an increase in P-gp levels was seen in the CEM/A7R line after a 24 h expo sure to 1 mu g ml(-1) daunorubicin or epirubicin. The rapid increase i n mdr1 expression after a short period of exposure to doxorubicin, dau norubicin or epirubicin suggests that induction of mdr1 expression may have an important role in the development of drug-resistant tumours.