title: Faslodex (ICI 182, 780), a novel estrogen receptor downregulator--future possibilities in breast cancer.
abstract: Tamoxifen is an effective treatment for breast cancer; however, as well as exerting antagonistic effects on the estrogen receptor (ER), tamoxifen acts as a partial agonists in estrogen-sensitive tissues, resulting in stimulation of the endometrium and tumor growth in some patients who become resistant to treatment.ICI 182, 780 (Faslodex), a steroidal estrogen antagonist, is the first in a new class of agent-an estrogen receptor downregulator. Pre-clinical breast cancer models show that ICI 182, 780 leads to a prolonged duration of response, and that it exerts its effects via a different mode of action to tamoxifen. This was confirmed in a small clinical study involving 19 post-menopausal advanced breast cancer patients, where ICI 182, 780 was highly effective after tamoxifen failure. Definitive evidence of the differing modes of action of ICI 182, 780 and tamoxifen, were provided in a study involving post-menopausal women with primary breast cancer, where analyses of tumor samples following short-term exposure to both drugs, showed that ICI 182, 780 reduced tumor ER levels in a dose-dependent manner, and to a significantly greater extent than tamoxifen. Additionally, unlike tamoxifen, ICI 182, 780 did not promote ER-mediated progesterone receptor expression, indicating that it lacks estrogen agonist activity. Ongoing studies in post-menopausal women with advanced breast cancer are comparing ICI 182, 780 to anastrozole and tamoxifen, respectively. Future studies being considered are whether ICI 182, 780 may also be effective in breast cancer in pre-menopausal women, in early breast cancer and in ductal carcinoma in situ in the breast, in combination with other hormonals, cytotoxics and biological modifiers.
authors.affiliation: Nottingham City Hospital, Hucknall Road, NG5 1PB, Nottingham, UK. john.robertson@nottingham.ac.uk
authors.forename: J F
authors.initials: JF
authors.lastname: Robertson
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol