Idarubicin overcomes P-glycoprotein-related multidrug resistance: comparison with doxorubicin and daunorubicin in human multiple myeloma cell lines

The clinical utility of anthracyclines like doxorubicin (DOX) and daunorubi cin (DNR) for treatment of multiple myeloma (MM) is limited by the occurren ce of multidrug resistance (MDR). Highly lipophilic anthracyclines like ida rubicin (IDA) might circumvent MDR and thereby enhance chemotherapeutic eff icacy. To determine the efficacy of IDA in myeloma cells, the pharmacokinet ics and cytotoxicity of IDA and its major metabolite idarubicinol (IDAol) w ere compared with those of DNR, DOX, and doxorubicinol (DOXol) in the cell line RPMI 8226-S and two MDR sublines (8226-R7 and 8226-Dox40) that overexp ress the drug transporter P-glycoprotein (Pgp). Cytotoxicity assays using M TT (viability) or annexin V (apoptosis) showed a 10-50-fold higher potency of IDA compared with DNR or DOX in the MDR variant cell lines. The differen ce in cytotoxicity was lower in the sensitive parental cell line (3-fold). These results are explained by a better intracellular uptake of IDA compare d to DNR in resistant 8226 cell lines. The Pgp-inhibitor verapamil affected IDA uptake only in the most resistant cell line 8226-Dox40. This indicates that IDA is less sensitive than DNR to transport-mediated MDR. IDAol was a t least 32-fold more cytotoxic than DOXol, and more susceptible to Pgp tran sport than IDA. These studies demonstrate that the efficacy of IDA in MDR M M cell lines is superior to that of DOX or DNR, and that IDA may become an important drug in the treatment of MM, especially in refractory disease. (C ) 1999 Elsevier Science Ltd. All rights reserved.