Models of new antioestrogen action in vivo: Primary tumours

We have conducted a clinical trial of the novel pure antioestrogen ICI 182780 to assess its short-term biological effects in women with primary breast cancer. The results were compared against those obtained from a similar study of tamoxifen. In both studies, the drugs were administered for a short period of time in the interval between first clinic attendance and operation. Samples of tumour tissue were obtained both before and after treatment with the antioestrogens. Seven days treatment with ICI 182780 caused a significant decrease in tumour proliferation as indicated by the Ki67 labelling index (Ki67LI). Tamoxifen caused a similar reduction in the Ki67LI after a median of 21 days treatment. In oestrogen receptor (ER) positive breast tumours, ICI 182780 caused a profound decrease in the level of receptor protein that could be detected immunocytochemically whereas tamoxifen was without effect. This reduction in ER-protein content was not reflected in a similar decrease in the mRNA for the receptor. ICI 182780 significantly reduced the expression of two oestrogen-regulated genes (the progesterone receptor and pS2) whereas tamoxifen was without effect. Finally, although ICI 182780 reduced ER expression to almost undetectable levels in some tumours, no other changes suggestive of an endocrine insensitive phenotype were apparent. In conclusion, ICI 182780 produces demonstrable antioestrogenic effects on human primary breast tumours in vivo and is without any oestrogen agonist effects. The novel mechanism of action of the new pure antioestrogen, as determined in vitro, is reflected in its effects on human primary breast tumours in vivo.