title: Comparison of the effects of EM-652 (SCH57068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast tumors in nude mice.
abstract: EM-652 exerts pure antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the antiestrogen most widely used for the treatment of breast cancer, exerts mixed antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.
authors.affiliation: Oncology and Molecular Endocrinology Research Center, Laval University Medical Center and Laval University, Quebec, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Gutman
authors.forename: Steeve
authors.initials: S
authors.lastname: Couillard
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.forename: Bernard
authors.initials: B
authors.lastname: Candas
authors.forename: Claude
authors.initials: C
authors.lastname: Labrie
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004717:Endometrium / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004970:Estrone / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017312:Toremifene / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D002934:Cinnamates; D004965:Estrogen Antagonists; D010880:Piperidines; D013267:Stilbenes; D013629:Tamoxifen; C038345:droloxifene; C087550:3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid; D004970:Estrone; C012121:ritetronium; C071362:idoxifene; D020849:Raloxifene Hydrochloride; D017312:Toremifene