The efflux of anthracyclines in multidrug-resistant cell lines.
In order to address the association of enhanced drug efflux with the multidrug-resistant (MDR) phenotype, we have studied the cellular pharmacokinetics of anthracyclines in the P-glycoprotein (Pgp)-positive MDR cell lines H69/LX4 (human small cell lung cancer) and EMT6/AR1.0 (mouse mammary tumour). Both doxorubicin (DOX) and daunorubicin (DNR) were accumulated to a lesser extent and effluxed at a higher rate by MDR cells than by their drug-sensitive counterparts. In contrast, the 9-alkyl substituted compound, aclacinomycin A (ACL), was accumulated and effluxed from parent and MDR cells at an identical rate. In experiments designed to examine energy-dependent efflux, DOX and DNR were shown to be efficiently effluxed against the concentration gradient in the presence of glucose. However, in the same experiments the analogues ACL and Ro 31-3294 (9-alkyl and morpholinyl substituted), which have previously been shown to retain activity against MDR cell lines, were accumulated and effluxed at identical rates in parent and MDR EMT6 cells. Hence, 9-alkyl and morpholinyl substituted compounds appear to behave less favourably as substrates for energy-driven drug efflux by Pgp-positive MDR cells than do DOX or DNR. Resistance modifiers verapamil and cyclosporin A appeared to abolish energy-dependent efflux for DOX and DNR in both the EMT6 and H69 MDR lines whereas they had no effect on the cellular efflux of ACL. The altered cellular pharmacology in MDR cell lines may provide a rational basis for the use of modified anthracycline analogues (e.g. 9-alkyl and morpholinyl (substituted) and resistance of modifying agent in the treatment of tumours expressing a Pgp-mediated phenotype.
Coley
H M
HM
MRC Clinical Oncology and Radiotherapeutics Unit, Cambridge, U.K.
Twentyman
P R
PR
Workman
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015250:Aclarubicin / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D010641:Phenotype; D014407:Tumor Cells, Cultured / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; C011157:aclacinomycins; C083892:Ro 313294; D015250:Aclarubicin; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; D003630:Daunorubicin