p170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives

Abstract

BACKGROUND. Cell sensitivity to anthracyclines and other drugs depends on several factors, including overexpression of a 170Kd transmembrane glycoprotein (P170) that enhances drug efflux from the cells. Since the result of treatment is negatively related to the expression of P170 in leukemia, malignant lymphoma and other tumors, it is important to investigate drugs and methods that can modify multidrug resistance (MDR). MATERIALS AND METHODS. Using an MTT-microcultured tetrazolium colorimetric method, we assayed sensitivity to daunorubicin (DNR) and to its 4-demethoxy derivative idarubicin (IDA) in two MDR cell lines (CEM VLB and LOVO DX) and in their respective non-MDR parental lines (CEM and LOVO 109), with and without three MDR modifiers, namely the D-isomer of verapamil (DVRP), cyclosporin A (CyA) and the new CyA derivative SDZ PSC 833. RESULTS. We showed that down-modulation of resistance with MDR modifiers was greater for DNR than for IDA in MDR cells. However, we also demonstrated that restoration of full sensitivity could only be achieved for IDA, not for DNR. DVRP and CyA in combination were more effective than either compound alone and could abolish P170-related resistance to IDA at concentrations of 1-2 microM and 1.6 microM, respectively. SDZ PSC 833 alone was even more effective and set MDR to zero at a concentration ranging between 0.8 and 1.6 microM. CONCLUSIONS. These data suggest that combinations of IDA and MDR modifiers may improve the results of cancer and leukemia treatment and that they are worth investigating in vivo, with attention to possible effects on drug pharmacokinetics and on normal tissue damage.