title: Antiestrogenic activity of DP-TAT-59, an active metabolite of TAT-59 against human breast cancer.
abstract: OBJECTIVE
  The purpose of this study was to clarify the mechanism(s) of antiestrogenic action of DP-TAT-59 ((Z)-2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropyl-phenyl)- 1-butenyl)phenoxy)-N,N-dimethylethylamine), the main active metabolite of TAT-59.
  
  
  METHODS
  Using 4-OH-tamoxifen (a hydroxylated metabolite of tamoxifen) as a reference compound, we examined the relationship between hormone-dependent tumor cells and DP-TAT-59 and characterized estrogen receptor (ER) complexes with DP-TAT-59 using ion-exchange chromatography.
  
  
  RESULTS
  DP-TAT-59 inhibited the in vitro proliferation of MCF-7 cells under serum-free conditions at a lower concentration than did 4-OH-tamoxifen. The conditioned medium (CM) obtained from the culture supernatant of MCF-7 cells in the presence of these antiestrogens suppressed the growth of ER-negative cell lines, but that from ER-negative human mammary carcinoma MX-1 cells did not. The CM from DP-TAT-59-treated cells showed a higher growth-inhibitory potency against human mammary carcinoma ZR-75-1 cells than did that from 4-OH-tamoxifen-treated cells. The growth-inhibitory potency of the CM was neutralized by the addition of the anti-TGF-beta antibody. The CM obtained from cells treated with DP-TAT-59 contained more TGF-beta and less TGF-alpha than that treated with 4-OH-tamoxifen. As the antiestrogenic activity of TAT-59 might be mediated through ER, the interaction of these antiestrogens with a cytoplasmic receptor of MCF-7 cells was examined. While the competitive binding of [3H]-estradiol with these antiestrogens to ER was similar, ER complexes with DP-TAT-59 showed a different elution profile by ion-exchange chromatography, indicating that DP-TAT-59 formed a different complex with ER from either 4-OH-tamoxifen or estradiol.
  
  
  CONCLUSIONS
  These findings suggest that at least a part of the growth suppressive ability of DP-TAT-59 against human mammary carcinoma might depend on the production of growth inhibitory factors and/or the suppression of production of growth factors from ER-positive cells, and that the production of growth inhibitory factors might be stimulated by ER complexes with antiestrogens rather than with estrogen.
authors.affiliation: Hanno Research Center, Taiho Pharmaceutical Co. Ltd., Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Toko
authors.forename: J
authors.initials: J
authors.lastname: Shibata
authors.forename: M
authors.initials: M
authors.lastname: Nukatsuka
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D001667:Binding, Competitive; D001692:Biological Transport; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D002852:Chromatography, Ion Exchange; D017077:Culture Media, Conditioned; D004958:Estradiol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D006801:Humans; D007700:Kinetics; D011960:Receptors, Estrogen / Q000302:isolation & purification / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D017077:Culture Media, Conditioned; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; C064635:TAT 59; C064590:2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropylphenyl)-1-butenyl)phenoxy)-N,N-dimethylethylamine; C016601:afimoxifene; D004958:Estradiol