Effects of cyclosporin A and verapamil on the intracellular daunorubicin accumulation in Chinese hamster ovary cells with increasing levels of drug-resistance.
Multidrug-resistance (MDR) is characterized by the presence of a 170 kDa glycoprotein (P-glycoprotein) in the plasma membrane. P-glycoprotein is thought to act as an efflux pump, leading to reduced drug accumulation in MDR cells. This defect in drug accumulation can be overcome by membrane transport modulating agents (MTMAs). We determined the concentration of MTMA needed for maximal restoration of daunorubicin content in 4 Chinese hamster ovary cell lines with increasing levels of drug-resistance using flow cytometry. Stimulation of daunorubicin accumulation occurred in a dose-dependent manner. The required level of MTMA needed for maximal drug accumulation increased with the level of drug-resistance. CHrA3 cells, which have a level of resistance comparable to clinical samples, needed relatively low concentrations of MTMA for maximal restoration of drug accumulation. This indicates that, in trial combining drugs and MTMAs, low dosages of MTMAs could be sufficient for optimal potentiation of cytotoxicity.
Silbermann
M H
MH
Radiobiological Institute TNO, Rijswijk, The Netherlands.
Boersma
A W
AW
Janssen
A L
AL
Scheper
R J
RJ
Herweijer
H
H
Nooter
K
K
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003524:Cyclosporins / Q000494:pharmacology* / Q000633:toxicity; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D012313:RNA / Q000032:analysis; D014700:Verapamil / Q000494:pharmacology* / Q000633:toxicity
D003524:Cyclosporins; D012313:RNA; D014700:Verapamil; D003630:Daunorubicin