Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution, and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells.
Four multidrug-resistant variants of the human squamous lung cancer cell line SW-1573 with levels of doxorubicin resistance ranging from 10- to 2000-fold were characterized with respect to drug accumulation and efflux, subcellular drug distribution pattern, antioxidant defenses, and P-glycoprotein expression. For all these parameters except the antioxidant defenses a correlation was observed with the level of doxorubicin resistance; with increasing drug resistance cellular drug accumulation capacity (as measured for doxorubicin) progressively decreased, initial drug efflux rates (as measured for daunorubicin) progressively increased, while the subcellular doxorubicin distribution (as measured by fluorescence microscopy) gradually shifted from a "mainly nuclear" to a "mainly cytoplasmic" pattern. Our data suggest that in the present set of cell lines the same mechanism of resistance is operating at all levels of doxorubicin resistance.
Keizer
H G
HG
Institute of Human Genetics, Free University, Amsterdam, The Netherlands.
Schuurhuis
G J
GJ
Broxterman
H J
HJ
Lankelma
J
J
Schoonen
W G
WG
van Rijn
J
J
Pinedo
H M
HM
Joenje
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism*; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D014700:Verapamil; D013482:Superoxide Dismutase; D003630:Daunorubicin