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 in the treatment of metastatic breast cancer and raloxifene, presently approved for use in postmenopausal women for the treatment of osteoporosis. Tamoxifen treatment of women leads to a small increase in the incidence of endometrial 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 class. Two such mechanisms have been proposed: (1) conversion of the drug to electrophilic metabolites that damage cellular DNA; and (2) an oestrogen agonist action on the uterus, promoting endogenous lesions. In rats, long-term tamoxifen treatment results in liver cancer via a genotoxic mechanism. However, it seems most likely that, in women treated with tamoxifen, endometrial cancer is related to an oestrogen agonist effect of this drug, promoting uterine cell proliferation.