Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens.

This investigation examines the tamoxifen (TAM)-dependent growth in vivo of an MCF-7 tumor variant, MCF-7TAM, previously reported in this journal (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988). Ovariectomized athymic mice were implanted with 1-mm3 pieces of MCF-7TAM and were treated with Silastic capsules of varying sizes containing TAM to demonstrate dose-dependent growth over a 10-wk experiment. TAM was necessary to maintain tumor growth. Animals whose capsules were removed at 6 wk showed complete tumor stasis after 20 wk of observation. Removal of TAM after 11 wk caused the rate of tumor growth to decrease compared with TAM-treated animals. Tumor areas were significantly different (P less than 0.03) at Wk 20. The growth of TAM-stimulated tumor, MCF-7TAM, was inhibited by the novel steroidal antiestrogens, ICI 164,384 and RU 39,411. TAM-stimulated growth (0.5-cm Silastic capsule) was maintained at control levels by 8 wk of treatment with ICI 164,384 (1 mg s.c. every other day). ICI 164,384 alone had no stimulatory activity. At the same dose, RU 39,411 inhibited TAM-stimulated growth of MCF-7TAM, although not to control levels. RU 39,411 was slightly stimulatory when administered alone. The growth of MCF-7TAM was stimulated by either TAM or 17 beta-estradiol. The antiestrogen, RU 39,411, effectively inhibited estradiol-stimulated tumor growth. Overall, these studies confirm and extend the previous observation on TAM-stimulated growth of breast cancer cells in vivo and demonstrate the possibility of developing novel antiestrogens to prevent this form of drug resistance should it occur in the clinic.