N-benzyladriamycin-14-valerate (AD 198)-resistant cells exhibit highly selective cross-resistance to other anthracyclines that circumvent multidrug resistance.
N-Benzyladriamycin-14-valerate (AD 198)-resistant murine J774.2 macrophage-like cells (A300) exhibited a novel mechanism of resistance in which P-glycoprotein was overexpressed without decreased AD 198 accumulation. Cross-resistance to Adriamycin (ADR), N-benzyladriamycin, and Adriamycin-14-valerate was due, at least in part, to reduced accumulation, suggesting that circumvention of P-glycoprotein-mediated transport was associated with extreme lipophilicity conferred by both substitutions. Thus, unlike multidrug resistance mediated by either P-glycoprotein, the multidrug resistance-associated protein (MRP), or decreased topoisomerase II activity, cross-resistance in A300 cells was highly structure-specific. In order to further characterize the specificity of AD 198 resistance, the cytotoxicity, accumulation, and intracellular localization of a series of 3'-morpholinyl, 3'-deamino and halogenated ADR congeners that have been reported to circumvent MDR was determined in AD 198-resistant J774.2 and P388 AD 198-resistant cells. Cross-resistance correlating with increased AD 198 resistance was observed for 2'-bromo-4'-epi-hydroxy-daunomycin (13-fold), morpholinyl doxorubicin (24-fold), and 4'-iodo-4'-deoxydoxorubicin (2.8-fold), but was attributable to decreased accumulation. Cross-resistance to 3'-hydroxy-14-O-palmitoyl-doxorubicin (6-fold) was not due to reduced accumulation. No cross-resistance was observed for the highly cytotoxic metabolite of WP474, 3'-hydroxyldoxorubicin (hydroxyrubicin; WP159), nor for the much less cytotoxic 3'-O-benzylated congeners, including 3'-O-benzyl-doxorubicin-14-valerate. These findings indicate that AD 198 resistance confers cross-resistance to compounds that, like AD 198, localize in the cytoplasm but are metabolized to highly cytotoxic, nuclear-localizing compounds.
Lothstein
L
L
Department of Pharmacology, University of Tennessee College of Medicine, Memphis 38163.
Hosey
L M
LM
Sweatman
T W
TW
Koseki
Y
Y
Dockter
M
M
Priebe
W
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002352:Carrier Proteins / Q000502:physiology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004351:Drug Resistance; D015251:Epirubicin / Q000031:analogs & derivatives*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D015251:Epirubicin; C042907:3'-deamino-3'-hydroxydoxorubicin; D004317:Doxorubicin; C046808:N-benzyladriamycin-14-valerate