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Title: Differential effects of estrogen, tamoxifen and the pure antiestrogen ICI 182,780 in human drug-resistant leukemia cell lines.
Austin 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
Publication information: 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.
Gov't Doc #: 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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