title: Common mechanism for the estrogen agonist and antagonist activities of droloxifene.
abstract: The incidence of postmenopausal osteoporosis is increasing as the population ages. Even though estrogen replacement therapy has proven beneficial in reducing the number of skeletal fractures, the known risks and associated side-effects of estrogen replacement therapy make compliance poor. Recent research has focused on the development of tissue specific estrogen agonist/antagonists such as droloxifene which can prevent estrogen deficiency-induced bone loss without causing uterine hypertrophy. 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 droloxifene that underlies its estrogen agonist and antagonist effects in different tissues. Droloxifene and estrogen, which have identical effects on bone in vivo, both induced p53 expression and apoptosis in cells of in vitro rat bone marrow cultures resulting in a decrease in the number of bone-resorbing osteoclasts. Droloxifene is growth inhibitory in MCF-7 human breast cancer cells and therefore acts as an antagonist, whereas estrogen is mitogenic to these cells and acts as an agonist. Droloxifene, but not estrogen, induced p53 expression and apoptosis in MCF-7 cells. These results indicate that the induction of apoptosis by droloxifene may be the common mechanism for both its estrogen agonist effects in bone and its antagonist effects in breast tissue.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer, Inc., Groton, Connecticut 06340, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Grasser
authors.forename: L C
authors.initials: LC
authors.lastname: Pan
authors.forename: D D
authors.initials: DD
authors.lastname: Thompson
authors.forename: V M
authors.initials: VM
authors.lastname: Paralkar
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D017209:Apoptosis; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells; D001943:Breast Neoplasms / Q000473:pathology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000819:agonists*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D039661:Integrin beta3; D010010:Osteoclasts / Q000187:drug effects; D010052:Ovariectomy; D010980:Platelet Membrane Glycoproteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D004965:Estrogen Antagonists; D004967:Estrogens; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D013629:Tamoxifen; C038345:droloxifene; D004958:Estradiol