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

Int J Cancer. 1993 Nov 11;55(5):873-6. doi: 10.1002/ijc.2910550529.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Breast Neoplasms / pathology*
  • Cell Division / drug effects
  • Drug Resistance*
  • Estradiol / analogs & derivatives*
  • Estradiol / metabolism
  • Estradiol / pharmacology
  • Fulvestrant
  • Humans
  • Receptors, Estrogen / metabolism
  • Tamoxifen / pharmacology*
  • Tumor Cells, Cultured


  • Receptors, Estrogen
  • Tamoxifen
  • Fulvestrant
  • Estradiol