DIFFERENTIAL-EFFECTS OF ESTROGEN, TAMOXIFEN AND THE PURE ANTIESTROGENICI-182,780 IN HUMAN DRUG-RESISTANT LEUKEMIA-CELL LINES

ICI 182,780, a potent, new steroidal antiestrogen without apparent ago nist activity, appears to be a potent modulator of the classic multidr ug resistance (MDR) phenotype in the CEM/A7, CEM/VLB(100) and K562/VIN 100 MDR cell lines. This reagent had no effect on the respective paren tal CCRF-CEM and K562 cell lines. The use of 1.25 mu M ICI 182,780 res ulted in a 6- to 7-fold decrease in doxorubicin resistance in the CEM/ A7 and CEM/VLB(100) cell lines. A dose-response effect was observed at ICI 182,780 concentrations of up to 5 mu M. As compared with tamoxife n (TAM), ICI 182,780 was 2 and 4 times more effective in the K562/VIN1 00 and CEM/A7 cell lines, respectively. ICI 182,780 at 0.625 mu M incr eased [H-3]-daunomycin uptake (P <0.0001) as effectively as 5 mu M TAM in the resistant CEM/A7 line. Drug-efflux studies showed that 5 mu M ICI 182,780 significantly decreased drug efflux as compared with 5 mu M TAM (P <0.0001). Estradiol (EST) at 10 mu M increased doxorubicin re sistance by 1.2-1.3 times in the CEM/A7 and CEM/VLB(100) cell lines an d significantly decreased drug accumulation (P = 0.002) and retention (P <0.001) in the CEM/A7 cell line. However, the addition of 10 mu M E ST to 1-2 mu M ICI 182,780 did not inhibit the ability of ICI 182,780 to modulate doxorubicin resistance in the two resistant cell lines. Us ing reverse-phase high-performance liquid chromatography (HPLC) to mea sure lipophilicity, we found no apparent association between the abili ty of ICI 182,780, TAM or EST to modulate resistance and their relativ e hydrophobicity.