COMMON MECHANISM FOR THE ESTROGEN AGONIST AND ANTAGONIST ACTIVITIES OF DROLOXIFENE

The incidence of postmenopausal osteoporosis is increasing as the popu lation ages. Even though estrogen replacement therapy has proven benef icial in reducing the number of skeletal fractures, the known risks an d associated side-effects of estrogen replacement therapy make complia nce poor. Recent research has focused on the development of tissue spe cific estrogen agonist/antagonists such as droloxifene which can preve nt estrogen deficiency-induced bone loss without causing uterine hyper trophy. Furthermore, droloxifene acts as a full estrogen antagonist on breast tissue and is being evaluated for treatment of advanced breast cancer. In this report we propose a common mechanism of action for dr oloxifene that underlies its estrogen agonist and antagonist effects i n different tissues. Droloxifene and estrogen, which have identical ef fects on bone in vivo, both induced p53 expression and apoptosis in ce lls of in vitro rat bone marrow cultures resulting in a decrease in th e number of bone-resorbing osteoclasts. Droloxifene is growth inhibito ry in MCF-7 human breast cancer cells and therefore acts as an antagon ist, whereas estrogen is mitogenic to these cells and acts as an agoni st. Droloxifene, but not estrogen, induced p53 expression and apoptosi s in MCF-7 cells. These results indicate that the induction of apoptos is by droloxifene may be the common mechanism for both its estrogen ag onist effects in bone and its antagonist effects in breast tissue. (C) 1997 Wiley-Liss, Inc.