title: [Antitumor activity of miproxifene phosphate (TAT-59) against human mammary carcinoma].
abstract: DP-TAT-59, an active metabolite of miproxifene phosphate (TAT-59), showed a strong anti-proliferating activity against ER-positive human mammary carcinoma cell lines, MCF-7 and T-47D, in the presence of 1 nM of estradiol. The ED50 value of DP-TAT-59 for each cell line was 30-fold lower than that of tamoxifen. TAT-59 suppressed the growth of mammary carcinoma, MCF-7 and Br-10, xenografted into nude mouse at a dose of 5 mg/kg/day, which is equivalent to 20 mg/body of daily dose to the patients. TAT-59 inhibited the growth of tamoxifen-resistant breast cancer cell lines, R-27 and FST-1, but not tamoxifen, suggesting the possible efficacy of TAT-59 for tamoxifen-refractory patients. DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 detected in blood after oral administration in the patients, exhibited equal growth-inhibitory activity against human mammary tumor xenograft, meaning the antitumor activity of TAT-59 may equally depend on these two metabolites. In uterotrophic testing using both immature mice and ovariectomized rats, while the effective dose of TAT-59 was lower than that of tamoxifen, TAT-59 showed dose-dependent estrogenic activity against their uteri, similar to tamoxifen. These results suggested that TAT-59 had a stronger antagonistic activity against estrogen-dependent mammary tumor than tamoxifen. We expect that TAT-59 will become an effective therapeutic agent for patients with high estrogen levels in their blood, such as premenopausal women, and the patients with whom the tamoxifen modality failed.
authors.affiliation: Hanno Research Center, Taiho Pharmaceutical Co., Ltd.
authors.forename: T
authors.initials: T
authors.lastname: Toko
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: A
authors.initials: A
authors.lastname: Fujioka
authors.forename: M
authors.initials: M
authors.lastname: Nukatuka
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: A
authors.initials: A
authors.lastname: Hashimoto
authors.forename: J
authors.initials: J
authors.lastname: Shibata
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000097:blood; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D004967:Estrogens; D013629:Tamoxifen; C064635:TAT 59