P-glycoprotein overexpression in mouse cells does not correlate with resistance to N-benzyladriamycin-14-valerate (AD 198).
The novel anthracycline N-benzyladriamycin-14-valerate (AD 198) circumvents P-glycoprotein (P-gp)- and altered topoisomerase II-mediated drug resistance. Nevertheless, AD 198-resistant (AD 198R) murine J774.2 cells overexpressed P-gp, were cross-resistant to other drugs through reduced accumulation and were rendered sensitive by continuous exposure to verapamil. Intracellular AD 198 was, however, similar in sensitive and resistant cells. Consequently, the ability of P-gp to confer AD 198 resistance was examined. It was observed that (i) AD 198 resistance in AD 198R cells grown without drug for 15 months declined by 60% with only a 10-15% loss of vinblastine cross-resistance and P-gp expression; (ii) a cloned AD 198R P388 mouse leukemic cell line did not express P-gp; and (iii) verapamil did not attenuate resistance against high-dose, short-term exposure to AD 198. Therefore, AD 198 resistance appeared to be P-gp-independent despite P-gp overexpression. Antioxidant enzyme and topoisomerase II activities remained unchanged between sensitive and resistance cells. These results suggest that AD 198 resistance was conferred by a novel mechanism.
Lothstein
L
L
Department of Pharmacology, University of Tennessee College of Medicine, Memphis 38163.
Koseki
Y
Y
Sweatman
T W
TW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000345:Affinity Labels; D000818:Animals; D001386:Azides; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000032:analysis*; D004095:Dihydropyridines; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D015151:Immunoblotting; D051379:Mice; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D004095:Dihydropyridines; C092567:adriamycin-14-valerate; C041130:azidopine; C062415:N-benzyladriamycin; D004317:Doxorubicin; C046808:N-benzyladriamycin-14-valerate; D014700:Verapamil; D004250:DNA Topoisomerases, Type II