Circumvention of tamoxifen resistance by the pure anti-estrogen ICI 182, 780

✍ Scribed by X. F. Hu; M. Veroni; M. de Luise; A. Wakeling; R. Sutherland; C. K. W. Watts; J. R. Zalcberg

• Book ID: 102277165
• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: French
• Weight: 413 KB
• Volume: 55
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.2910550529

✦ Synopsis

Both primary and acquired resistance to the growthinhibitory 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 5-2 I, and a tamoxifen-resistant line, MCF 5-23. Compared with tamoxifen, ICI 182,780 appeared to be I50 and I540 times more effective in inhibiting cell growth in the 5-2 I and 5-23 sub-lines respectively. ICI 182,780 completely circumvented tamoxifen resistance at a concentration of (5 to 10) X M in this model. Based on ICs0 concentrations, the 5-23 line was 22-fold more resistant to tamoxifen than the 5-2 I 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 K, 0.48 and 0.15 X 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 'H-estradiol binding were 2.3 x 10-8 M and I X M, respectively (cf. estradiol 0.89 X 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.