EFFECTS OF 4-HYDROXYTAMOXIFEN AND A NOVEL PURE ANTIESTROGEN (ICI-182780) ON THE CLONOGENIC GROWTH OF HUMAN BREAST-CANCER CELLS IN-VITRO

We have investigated the effects on breast cancer cell growth of 4-hyd roxytamoxifen (4OHT), a conventional antioestrogen with agonist activi ty, and 7 opentylsulphinyl)nonyl]oestra-1,3,5,(10)-triene-3, 17 beta-d iol (ICI 182780), a novel, pure antioestrogen, using established human breast cancer cell lines and cancer cells obtained directly from brea st cancer patients with malignant pleural effusions who had relapsed o n tamoxifen. The effects of the two agents were assessed using the Cou rtenay-Mills clonogenic assay, which measures the growth of single can cer cells as colonies suspended in soft agar. The standard assay was m odified by the use of defined serum- and phenol red-free growth medium . The growth of oestrogen receptor (ER)-positive MCF-7 cells in the as say was oestrogen responsive. Both antioestrogens inhibited the stimul atory effects of 1 nM oestradiol, but ICI 182780 caused significantly greater inhibition than 4OHT at 0.1-1.0 mu M concentrations. In the ab sence of oestradiol, 4OHT but not ICI 182780 caused significant stimul ation of colony formation at low (0.01-1.00 nM) concentrations. Neithe r antioestrogen had any effects on colony formation by the ER-negative Hs578T cell line. Successful colony formation was obtained in primary cultures from six out of eight malignant effusions. Colony formation was significantly stimulated by 0.1 nM oestradiol in four cases and by 10 nM 40HT in two cases. In contrast, ICI 182780 exhibited no intrins ic stimulatory activity and significantly inhibited both oestradiol- a nd 40HT-stimulated cell growth. We conclude that the agonist activity of 40HT and other conventional antioestrogens may cause treatment fail ure in some patients by stimulating breast cancer cell growth. The new , pure antioestrogen ICI 182780 is a more potent oestrogen antagonist than 4OHT and exhibits no growth-stimulatory activity. This agent may therefore offer therapeutic advantages over conventional antioestrogen s in patients with advanced breast cancer and may be effective after c onventional agents have failed.