ALTERATIONS OF VINBLASINE INFLUX IN MULTIDRUG-RESISTANT LYMPHOBLASTICLEUKEMIC CEM CELLS

Typical mutlidrug-resistant (MDR) CEM/VLB(100) cells exhibited reduced uptake of vinblastine (VLB) compared to their sensitive CEM counterpa rts, mean results were respectively, 3.19 and 35.4 pmol per 10(6) cell s. In CEM cells, the efflux of drug reached a steady state after 10-15 min while in CEM/VLB(100) cells, the typical P170-mediated efflux was still efficient after 40 min. Nevertheless, the most striking differe nce observed in CEM/VLB(100) cells was a dramatic decrease in early (3 0 sec) influx of drug which was 10 times lover than in sensitive cells , a characteristic still observed in the presence of Na azide and abse nce of glucose. MDR modulators increased influx in MDR cells without l ittle or no effect on sensitive cells. The Q(10) entry of VLB into sen sitive 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. Verap amil or nigericin, which rapidly increased the accumulation of VLB rai sed the Q(10) to >2. These results suggest that the primary defect in MDR cells would be an inhibition of influx, which might involve intera ctions with P170 through a reversible process.