title: Reversal of P-glycoprotein-mediated multidrug resistance by pure anti-oestrogens and novel tamoxifen derivatives.
abstract: In this study the ability of five novel anti-oestrogens [4-iodotamoxifen, pyrrolidino-4-iodotamoxifen, ethyl bromide tamoxifen (EBTx), ICI 164,384 (ICI 164) and ICI 182,780] to alter drug toxicity to multidrug resistant cell lines have been compared. The effect of these compounds on ATP-dependent vinblastine (VBL) transport was also tested using inside-out vesicles (IOV) prepared from highly P-glycoprotein (Pgp)-expressing CCRF-CEM/VBL1000 cells. The pure anti-oestrogen ICI 164 was most effective, enhancing doxorubicin and VBL toxicity to MCF-7Adr cells 25- and 35-fold, respectively, and was also the best inhibitor of ATP-dependent [3H]VBL accumulation by IOV. Pure anti-oestrogens, tamoxifen and iodotamoxifens completely reversed VBL resistance in the mdr1 transfected lung cancer cell line, S1/1.1, where resistance relative to wild-type cells was mediated solely by Pgp. The membrane impermeant tamoxifen derivative EBTx did not modify drug resistance, yet was as effective an inhibitor of VBL accumulation by inside-out Pgp-positive vesicles as tamoxifen. This indicates an intracellular role for tamoxifen and its derivatives in the modulation of Pgp-mediated drug resistance.
authors.affiliation: Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, U.K.
authors.forename: J
authors.initials: J
authors.lastname: Kirk
authors.forename: S K
authors.initials: SK
authors.lastname: Syed
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: M
authors.initials: M
authors.lastname: Jarman
authors.forename: B D
authors.initials: BD
authors.lastname: Roufogalis
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000633:toxicity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D004965:Estrogen Antagonists; D008562:Membrane Glycoproteins; D013629:Tamoxifen; D014747:Vinblastine