title: Circumvention of tamoxifen resistance by the pure anti-estrogen ICI 182,780.
abstract: Both primary and acquired resistance to the growth-inhibitory effects of anti-estrogens (e.g., tamoxifen) limits the clinical usefulness of these drugs in the treatment of breast cancer. The new, steroidal anti-estrogen ICI 182,780 was tested for its ability to inhibit the proliferation of a tamoxifen-resistant variant of the parental MCF-7 human breast-cancer cell line. Two cell lines cloned from the MCF-7 line were used for these experiments: a tamoxifen-sensitive line, MCF 5-21, and a tamoxifen-resistant line, MCF 5-23. Compared with tamoxifen, ICI 182,780 appeared to be 150 and 1540 times more effective in inhibiting cell growth in the 5-21 and 5-23 sub-lines respectively. ICI 182,780 completely circumvented tamoxifen resistance at a concentration of (5 to 10) x 10(-9) M in this model. Based on IC50 concentrations, the 5-23 line was 22-fold more resistant to tamoxifen than the 5-21 line, but only 2-fold more resistant to ICI 182,780, reducing relative resistance by 10-fold in the resistant line. There were no differences in ER parameters between the 2 lines. ER numbers/cell were: 40500 and 34800 and the KD 0.48 and 0.15 x 10(-9) M in the 5-21 and 5-23 cells respectively. In the 5-23 cells, the concentrations of ICI 182,780 and tamoxifen resulting in a 50% inhibition of 3H-estradiol binding were 2.3 x 10(-8) M and 1 x 10(-6) M, respectively (cf. estradiol 0.89 x 10(-9) M). Thus, one potential mechanism for the increased effectiveness of ICI 182,780 may relate to the increased affinity of this drug for the estrogen receptor as compared with tamoxifen.
authors.affiliation: Department of Medicine, Heidelberg Repatriation Hospital, Vic., Australia.
authors.forename: X F
authors.initials: XF
authors.lastname: Hu
authors.forename: M
authors.initials: M
authors.lastname: Veroni
authors.forename: M
authors.initials: M
authors.lastname: De Luise
authors.forename: A
authors.initials: A
authors.lastname: Wakeling
authors.forename: R
authors.initials: R
authors.lastname: Sutherland
authors.forename: C K
authors.initials: CK
authors.lastname: Watts
authors.forename: J R
authors.initials: JR
authors.lastname: Zalcberg
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol