The novel anti-oestrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-oestrogen resistance

Abstract

Summary The effect of idoxifene, a novel anti-oestrogen with less agonist activity than tamoxifen, was compared with that of tamoxifen on the growth of hormone-dependent MCF-7 breast cancer xenografts. Forty tumours were established with oestradiol support in ovariectomized athymic mice, allowed to grow to a median volume of 420 mm3 and then continued with 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 withdrawal 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 acquired resistance compared with 3/10 tumours treated with tamoxifen. In separate experiments, 94 animals were treated initially with oestradiol, tamoxifen, idoxifene or placebo following implantation with 1-mm3 pieces of either wild-type (WT) or tamoxifen-resistant (TR) MCF-7 tumour. After 4 months, only 1/11 WT tumours became established with idoxifene compared with 4/11 with tamoxifen, 8/12 with oestradiol and 0/12 with placebo. Likewise, fewer TR tumours were supported by idoxifene (3/12) than by tamoxifen (8/12) or oestrogen (11/12). These data indicate that, compared with tamoxifen, idoxifene shows reduced growth support of MCF-7 xenografts and may share only partial cross-resistance. Furthermore, the development of acquired anti-oestrogen resistance may be reduced during long-term idoxifene therapy. The drug's reduced agonist activity may, in part, explain these observations and indicate a preferable biochemical profile for breast cancer treatment.

Emerging Therapies for the Prevention or Treatment of Postmenopausal Osteoporosis

“…Tamoxifen strongly antagonizes the estrogen-stimulated proliferation of mammary tissue and is prescribed successfully to treat and prevent breast cancer. ,− However, tamoxifen functions as a partial estrogen agonist in uterine tissues with a 5-fold increased risk of endometrial cancer. − Additionally, tamoxifen has been shown to induce DNA adduct formation , and liver cancer in rats . Toremifene, idoxifene, and droloxifene are more recent triphenylethylenes with reduced or nondetectable DNA adduct formation. − All three stimulate uterine hypertrophy to a lesser degree than tamoxifen in animal studies , and are being evaluated for the prevention or treatment of breast cancer. Toremifene lowered cholesterol levels and prevented bone loss in postmenopausal breast cancer patients but appeared to be as estrogenic in the uterus as tamoxifen .…”

“…131 Toremifene, idoxifene, and droloxifene are more recent triphenylethylenes with reduced or nondetectable DNA adduct formation. [132][133][134][135][136][137][138][139] All three stimulate uterine hypertrophy to a lesser degree than tamoxifen in animal studies 140,141 and are being evaluated for the prevention or treatment of breast cancer. Toremifene lowered cholesterol levels and prevented bone loss in postmenopausal breast cancer patients but appeared to be as estrogenic in the uterus as tamoxifen.…”

ICI 182,780 (Faslodex?)

“…The success of tamoxifen is based on the beneficial combination of therapeutic efficacy and a modest level of side effects. A number of other nonsteroidal antiestrogens have been described in the literature, including toremifene,15 droloxifene,16 idoxifene,17 raloxifene,18 and EM‐800 19. To date, none of these has been proven to offer significant advantages over tamoxifen in terms of either efficacy or tolerance.…”

Advances in the Science of Estrogen Receptor Modulation

“…Idoxifene also demonstrates antagonism of estradiol dependent MCF-7 breast cancer growth by sustained induction of apoptosis [113] as reported for tamoxifen [114]. Idoxifene may also reduce the development of acquired anti-estrogen resistance [115]. Due to a lack of demonstrable additional efficacy clinical trials have been discontinued for breast cancer and osteoporosis indications even though idoxifene had displayed activity against tamoxifen resistant breast cancer cell lines.…”