title: Differential effects of estrogen, tamoxifen and the pure antiestrogen ICI 182,780 in human drug-resistant leukemia cell lines.
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.
authors.affiliation: Department of Medicine, Heidelberg Repatriation Hospital, Victoria, Australia.
authors.forename: J R
authors.initials: JR
authors.lastname: Zalcberg
authors.forename: X F
authors.initials: XF
authors.lastname: Hu
authors.forename: M
authors.initials: M
authors.lastname: Ching
authors.forename: A
authors.initials: A
authors.lastname: Wakeling
authors.forename: D M
authors.initials: DM
authors.lastname: Wall
authors.forename: I C
authors.initials: IC
authors.lastname: Marschner
authors.forename: M
authors.initials: M
authors.lastname: de Luise
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000187:drug effects; D009363:Neoplasm Proteins / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004965:Estrogen Antagonists; D004967:Estrogens; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D004317:Doxorubicin