Retention of activity by selected anthracyclines in a multidrug resistant human large cell lung carcinoma line without P-glycoprotein hyperexpression.
A subline (COR-L23/R) of the human large cell lung line [corrected] COR-L23, derived by in vivo exposure to doxorubicin, exhibits an unusual multidrug resistant (MDR) phenotype. This subline shows cross-resistance to daunorubicin, vincristine, colchicine and etoposide but does not express P-glycoprotein. Interestingly, COR-L23/R [corrected] shows little or no resistance to a range of structurally-modified analogues of doxorubicin comprising 9-alkyl and/or sugar modified anthracyclines. We have previously identified these same compounds as effective agents against P-glycoprotein-positive MDR cell lines. In contrast to typical MDR cell lines, COR-L23/R [corrected] shows only minimal chemosensitisation by verapamil and no collateral sensitivity to verapamil. Compared to the parental cell line, COR-L23/R [corrected] displays reduced accumulation of doxorubicin and daunorubicin. Accumulation defects were apparent only after 0.5-1 h of incubation of cells with these agents. The rate of daunorubicin efflux was shown to be enhanced by COR-L23/R [corrected] and this efflux was demonstrated to be energy-dependent. The use of anthracyclines which retain activity in MDR cells thus appears to be a valid approach for the circumvention of MDR, not only in cells which express P-glycoprotein, but also where defective drug accumulation is due to other mechanisms possibly involving an alternative multidrug transporter.
Coley
H M
HM
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK.
Workman
P
P
Twentyman
P R
PR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D003630:Daunorubicin / Q000493:pharmacokinetics; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000032:analysis*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D008562:Membrane Glycoproteins; D014700:Verapamil; D003630:Daunorubicin