Anti-oestrogenic drugs and endometrial cancers

Tamoxifen is one of the most effective drugs to be used in the treatment of women with breast cancer and as a chemopreventive agent in women 'at risk' from this disease. Tamoxifen can be regarded as a paradigm for a new range of selective oestrogen receptor modulators that include toremifene, used i n the treatment of metastatic breast cancel and raloxifene, presently appro ved for use in postmenopausal women for the treatment of osteoporosis. Tamo xifen treatment of women leads to a small increase in the incidence of endo metrial cancers. It is important to understand the mechanism for this side effect in order to predict the likely human risk for other drugs of this cl ass. Two such mechanisms have been proposed: (1) conversion of the drug to electrophilic metabolites that damage cellular DNA; and (2) an oestrogen ag onist action on the uterus, promoting endogenous lesions. In rats, long-ter m tamoxifen treatment results in liver cancer via a genotoxic mechanism. Ho wever. it seems most likely that, in women treated with tamoxifen, endometr ial cancer is related to an oestrogen agonist effect of this drug, promotin g uterine cell proliferation. (C) 2001 Elsevier Science Ireland Ltd. All ri ghts reserved.