THE NOVEL ANTIESTROGEN IDOXIFENE INHIBITS THE GROWTH OF HUMAN MCF-7 BREAST-CANCER XENOGRAFTS AND REDUCES THE FREQUENCY OF ACQUIRED ANTIESTROGEN RESISTANCE

The effect of idoxifene, a novel anti-oestrogen with less agonist acti vity than tamoxifen, was compared with that of tamoxifen on the growth of hormone-dependent MCF-7 breast cancer xenografts. Forty tumours we re established with oestradiol support in ovariectomized athymic mice, allowed to grow to a median volume of 420 mm(3) and then continued wi th oestradiol, no support, tamoxifen or idoxifene delivered by 1.5-cm silastic capsule. Tumour regression occurred with both anti-oestrogens , although maximum regression was observed following oestradiol withdr awal alone. While prolonged anti-oestrogen therapy was associated with static growth, tumour volumes were significantly lower with idoxifene (P=0.01). After 6 months, 0/10 idoxifene-treated tumours developed ac quired resistance compared with 3/10 tumours treated with tamoxifen. I n separate experiments, 94 animals were treated initially with oestrad iol, tamoxifen, idoxifene or placebo following implantation with 1-mm( 3) pieces of either wild-type (WT) or tamoxifen-resistant (TR) MCF-7 t umour. After 4 months, only 1/11 WT tumours became established with id oxifene compared with 4/11 with tamoxifen, 8/12 with oestradiol and 0/ 12 with placebo, Likewise, fewer TR tumours were supported by idoxifen e (3/12) than by tamoxifen (8/12) or oestrogen (11/12). These data ind icate that, compared with tamoxifen, idoxifene shows reduced growth su pport of MCF-7 xenografts and may share only partial cross-resistance. Furthermore, the development of acquired anti-oestrogen resistance ma y be reduced during long-term idoxifene therapy. The drug's reduced ag onist activity may, in part, explain these observations and indicate a preferable biochemical profile for breast cancer treatment.