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Title: Differential effects of estrogen, tamoxifen and the pure antiestrogen ICI 182,780 in human drug-resistant leukemia cell lines.
Authors: Zalcberg, John R;Hu, X F;Ching, M S;Wakeling, A;Wall, D M;Marschner, I C;de Luise, M
Affiliation: Department of Medicine, Heidelberg Repatriation Hospital, Victoria, Australia.
Issue Date: 16-May-1993
Citation: Cancer Chemotherapy and Pharmacology; 33(2): 123-9
Abstract: 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.
Internal ID Number: 7903222
Type: Journal Article
Subjects: Antineoplastic Agents.pharmacology
Carrier Proteins.drug effects
Drug Resistance
Estradiol.analogs & derivatives.pharmacology
Estrogen Antagonists.pharmacology
Leukemia.drug therapy
Membrane Glycoproteins.drug effects
Neoplasm Proteins.drug effects
Time Factors
Tumor Cells, Cultured
Appears in Collections:Journal articles

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