REVERSAL OF P-GLYCOPROTEIN-MEDIATED MULTIDRUG-RESISTANCE BY PURE ANTIESTROGENS AND NOVEL TAMOXIFEN DERIVATIVES

In this study the ability of five novel anti-oestrogens [4-iodotamoxif en, pyrrolidino-4-iodotamoxifen, ethyl bromide tamoxifen (EBTx), ICI 1 64,384 (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 in side-out vesicles (IOV) prepared from highly P-glycoprotein (Pgp)-expr essing CCRF-CEM/VBL(1000) cells. The pure anti-oestrogen ICI 164 was m ost effective, enhancing doxorubicin and VBL toxicity to MCF-7(Adr) ce lls 25- and 35-fold, respectively, and was also the best inhibitor of ATP-dependent [H-3]VBL accumulation by IOV. Pure anti-oestrogens, tamo xifen and iodotamoxifens completely reversed VBL resistance in the mdr 1 transfected lung cancer cell line, S1/1.1, where resistance relative to wild-type cells was mediated solely by Pgp. The membrane impermean t 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 tamox ifen and its derivatives in the modulation of Pgp-mediated drug resist ance.