Alterations of vinblastine influx in multidrug-resistant lymphoblastic leukaemic CEM cells.
Typical multidrug-resistant (MDR) CEM/VLB100 cells exhibited reduced uptake of vinblastine (VLB) compared to their sensitive CEM counterparts mean results were respectively, 3.19 and 35.4 pmol per 10(6) cells. In CEM cells, the efflux of drug reached a steady state after 10-15 min while in CEM/VLB100 cells, the typical P170-mediated efflux was still efficient after 40 min. Nevertheless, the most striking difference observed in CEM/VLB100 cells was a dramatic decrease in early (30 sec) influx of drug which was 10 times lower than in sensitive cells, a characteristic still observed in the presence of Na azide and absence of glucose. MDR cells without little or no effect on sensitive cells. The Q10 entry of VLB into sensitive cells was 1.2 while it was 2.2 in CEM, suggesting that the mode of entry of VLB into MDR cells differed from that of CEM cells. Verapamil or nigericin, which rapidly increased the accumulation of VLB raised the Q10 to >2. These results suggest that the primary defect in MDR cells would be an inhibition of influx, which might involve interactions with P170 through a reversible process.
Colin
M
M
GIBSA, EA 1238, Laboratoire de Biochimie, UFR de Pharmacie, 51, Reims, France.
Madoulet
C
C
Warren
L
L
Jardillier
J C
JC
D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism*; D013696:Temperature; D014316:Tritium; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000493:pharmacokinetics* / Q000494:pharmacology
D014316:Tritium; D014747:Vinblastine