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.
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Authors | J Kirk, S K Syed, A L Harris, M Jarman, B D Roufogalis, I J Stratford, J Carmichael |
Journal | Biochemical pharmacology
(Biochem Pharmacol)
Vol. 48
Issue 2
Pg. 277-85
(Jul 19 1994)
ISSN: 0006-2952 [Print] England |
PMID | 7914404
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Carrier Proteins
- Estrogen Antagonists
- Membrane Glycoproteins
- Tamoxifen
- Vinblastine
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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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