Long-term inhibitory effect of the orally active and pure antiestrogen EM-800 on the growth of human breast cancer xenografts in nude mice

The antiproliferative effect of the new antiestrogen EM-800 has been studied during 40 weeks of treatment on human breast carcinoma ZR-75-1 xenografts in ovariectomized nude mice supplemented with estrone (0.5 microg, s.c. daily). At the daily 50 microg (approximately 2.5 mg/kg) oral dose, EM-800 caused a complete inhibition of the 680% stimulatory effect of estrone on the growth of the ZR-75-1 human breast cancer xenografts. Complete response, defined as the complete disappearance of the tumors, was observed in 41% of tumors following treatment with the 50 microg dose of the antiestrogen, while a value of 26% was found in ovariectomized animals. The proportion of tumors showing progression at the end of 40 weeks of treatment decreased from 94% in the estrone-supplemented animals to 62%, 61% and 19% in the animals receiving the 5 microg, 20 microg and 50 microg daily doses of the antiestrogen, respectively. None of the tumors that showed a complete or a partial response progressed at later time intervals. The 50 microg daily dose of EM-800 nearly completely (93%) or completely (28% below the value in ovariectomized animals) reversed the stimulatory effect of estrone on uterine and vaginal weight, respectively. The disappearance of 41% of tumors in the group of animals that received the 50 microg daily dose of EM-800 indicates that the antiestrogen induces cell death or apoptosis in ZR-75-1 human breast cancer cells and that its action is cytotoxic and not only cytostatic.