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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.
AuthorsJ Kirk, S K Syed, A L Harris, M Jarman, B D Roufogalis, I J Stratford, J Carmichael
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 48 Issue 2 Pg. 277-85 (Jul 19 1994) ISSN: 0006-2952 [Print] England
PMID7914404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carrier Proteins
  • Estrogen Antagonists
  • Membrane Glycoproteins
  • Tamoxifen
  • Vinblastine
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carrier Proteins (physiology)
  • Cell Division (drug effects)
  • Drug Resistance
  • Estrogen Antagonists (pharmacology)
  • Humans
  • Membrane Glycoproteins (physiology)
  • Tamoxifen (analogs & derivatives)
  • Tumor Cells, Cultured (drug effects)
  • Vinblastine (toxicity)

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