Zalcberg J R, Hu X F, Ching M, Wakeling A, Wall D M, Marschner I C, de Luise M
Department of Medicine, Heidelberg Repatriation Hospital, Victoria, Australia.
Cancer Chemother Pharmacol. 1993;33(2):123-9. doi: 10.1007/BF00685329.
ICI 182,780, a potent, new steroidal antiestrogen without apparent agonist activity, appears to be a potent modulator of the classic multidrug resistance (MDR) phenotype in the CEM/A7, CEM/VLB100 and K562/VIN100 MDR cell lines. This reagent had no effect on the respective parental CCRF-CEM and K562 cell lines. The use of 1.25 microM ICI 182,780 resulted in a 6- to 7-fold decrease in doxorubicin resistance in the CEM/A7 and CEM/VLB100 cell lines. A dose-response effect was observed at ICI 182,780 concentrations of up to 5 microM. As compared with tamoxifen (TAM), ICI 182,780 was 2 and 4 times more effective in the K562/VIN100 and CEM/A7 cell lines, respectively. ICI 182,780 at 0.625 microM increased [3H]-daunomycin uptake (P < 0.0001) as effectively as 5 microM TAM in the resistant CEM/A7 line. Drug-efflux studies showed that 5 microM ICI 182,780 significantly decreased drug efflux as compared with 5 microM TAM (P < 0.0001). Estradiol (EST) at 10 microM increased doxorubicin resistance by 1.2-1.3 times in the CEM/A7 and CEM/VLB100 cell lines and significantly decreased drug accumulation (P = 0.002) and retention (P < 0.001) in the CEM/A7 cell line. However, the addition of 10 microM EST to 1-2 microM ICI 182,780 did not inhibit the ability of ICI 182,780 to modulate doxorubicin resistance in the two resistant cell lines. Using reverse-phase high-performance liquid chromatography (HPLC) to measure lipophilicity, we found no apparent association between the ability of ICI 182,780, TAM or EST to modulate resistance and their relative hydrophobicity.
ICI 182,780是一种新型强效甾体抗雌激素药物，无明显激动剂活性，它似乎是CEM/A7、CEM/VLB100和K562/VIN100多药耐药（MDR）细胞系中经典MDR表型的有效调节剂。该试剂对相应的亲本CCRF-CEM和K562细胞系无作用。使用1.25微摩尔/升的ICI 182,780可使CEM/A7和CEM/VLB100细胞系中的阿霉素耐药性降低6至7倍。在ICI 182,780浓度高达5微摩尔/升时观察到剂量反应效应。与他莫昔芬（TAM）相比，ICI 182,780在K562/VIN100和CEM/A7细胞系中的效力分别高2倍和4倍。在耐药的CEM/A7细胞系中，0.625微摩尔/升的ICI 182,780增加[3H]柔红霉素摄取（P < 0.0001）的效果与5微摩尔/升的TAM相同。药物外排研究表明，与5微摩尔/升的TAM相比，5微摩尔/升的ICI 182,780显著降低药物外排（P < 0.0001）。10微摩尔/升的雌二醇（EST）使CEM/A7和CEM/VLB100细胞系中的阿霉素耐药性增加1.2至1.3倍，并显著降低CEM/A7细胞系中的药物积累（P = 0.002）和滞留（P < 0.001）。然而，在1至2微摩尔/升的ICI 182,780中加入10微摩尔/升的EST并不抑制ICI 182,780调节两种耐药细胞系中阿霉素耐药性的能力。使用反相高效液相色谱（HPLC）测量亲脂性，我们发现ICI 182,780、TAM或EST调节耐药性的能力与其相对疏水性之间无明显关联。
