The novel anti-oestrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-oestrogen resistance.
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.
Johnston
S R
SR
Department of Academic Biochemistry, Royal Marsden Hospital, London, UK.
Riddler
S
S
Haynes
B P
BP
A'Hern
R
R
Smith
I E
IE
Jarman
M
M
Dowsett
M
M
D000818:Animals; D001943:Breast Neoplasms / Q000097:blood / Q000517:prevention & control*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000517:prevention & control*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
D004965:Estrogen Antagonists; D013629:Tamoxifen; C071362:idoxifene; D004958:Estradiol