Similarities and distinctions in the mode of action of different classes of antioestrogens.

Abstract

Since the description of the first antioestrogen, MER 25, more than four decades ago (Lerner et al. 1958), and of tamoxifen ten years later (Harper & Walpole 1967a,b), a large number of antioestrogens with diverse chemical structures have been described in the literature. The high level of interest in the synthesis and testing of new antioestrogens has been sustained by the therapeutic and commercial success of tamoxifen in the treatment of breast cancer. More recently, the first demonstration that tamoxifen can reduce the incidence of breast cancer in healthy women at high risk of developing the disease (Fisher et al. 1998) and that raloxifene can prevent osteoporosis (Bryant & Dere 1998) have provided a new impetus for drug discovery. Of the many analogues of tamoxifen described, only one other, chlorotamoxifen (toremiphene, Kangas 1990), has been marketed for breast cancer whilst several others are in various stages of clinical evaluation (e.g. idoxifene, Coombes et al. 1995; droloxifene, Bruning 1992). These molecules have very similar chemical and pharmacological properties: they are all non-steroidal, triphenylethylene-derived structures and all are partial agonists (mixed agonist/antagonist activities). A number of other non-steroidal structures with antioestrogenic activity have been reported, including substituted tetrahydronaphthalenes (e.g. nafoxidene, Duncan et al. 1963; trioxifene, Jones et al. 1979), indole derivatives (e.g. zindoxifene, Stein et al. 1990; ZK 119010, von Angerer 1990), benzothiophenes (e.g. LY117018, Black & Good 1980; LY156758 (keoxifene), Clemens et al. 1983) and benzopyrans (Sharma et al. 1990, Grese et al. 1996). All of these antioestrogens share with tamoxifen the pharmacological characteristic of partial-agonist activity; thus, whilst they antagonise the trophic action of oestrogens, this activity is incomplete because each compound has intrinsic oestrogen-like stimulatory (agonist) activity in vivo. The effect of drug treatment is a balance between agonist and antagonist activity. Whilst the term ‘partial-agonist’ accurately conveys the idea that all of these antioestrogens have some oestrogenic activity, it does not adequately describe their complex organ, cell and