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

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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) × 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 × 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 3 H‐estradiol binding were 2.3 × 10−8 M and 1 × 10−6 M, respectively (cf. estradiol 0.89 × 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.