title: Estrogen agonistic/antagonistic effects of miproxifene phosphate (TAT-59)
abstract: OBJECTIVE
  We evaluated miproxifene phosphate (TAT-59) to elucidate its efficacy in antiestrogen therapy for breast cancer patients and to assess its tissue-selective estrogenic/antiestrogenic activity.
  
  
  METHODS
  Using DP-TAT-59, a major and active metabolite of TAT-59, an in vitro cell growth inhibition test was performed. Antitumor activity was determined using TAT-59 against human tumor xenografts of the MCF-7 and the Br-10 cell lines and MCF-7-derived tamoxifen-resistant cell lines, R-27 and FST-1. The antitumor activity of DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 found in human blood following a TAT-59 dose, was also examined after intravenous administration to experimental animals. The residual estrogenic activity of TAT-59, evaluated in terms of bone and lipid metabolism in ovariectomized rats, was then compared with that of tamoxifen.
  
  
  RESULTS
  DP-TAT-59 significantly inhibited the proliferation of estrogen receptor-positive MCF-7 and T-47D tumor cells in the presence of 1 nM estradiol. TAT-59, given to mice bearing MCF-7 or Br-10 xenografts, at the dose level of 5 mg/kg, exerted a significant growth inhibitory effect that was stronger than that of tamoxifen. Moreover, R-27 and FST-1 tumors, which show a resistance to tamoxifen, responded strongly to TAT-59, suggesting that TAT-59 might be effective against tumors resistant to tamoxifen. The metabolites of TAT-59, DP-TAT-59 and DM-DP-TAT-59, showed similar antitumor activity. Both TAT-59 and tamoxifen suppressed the decrease in bone density and reduced the blood cholesterol levels in ovariectomized rats, suggesting that the estrogenic activity of TAT-59 is comparable to that of tamoxifen.
  
  
  CONCLUSIONS
  On the basis of the above results, one may expect TAT-59 to become an effective drug in patients with tumors less sensitive to tamoxifen, while its estrogenic activity as determined by bone and lipid metabolism is similar to that of tamoxifen.
authors.affiliation: Hanno Research Center, Taiho Pharmaceutical Co., Ltd., 1-27 Misugidai, Hanno-City, Saitama, 357-8527, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Shibata
authors.forename: T
authors.initials: T
authors.lastname: Toko
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: A E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.forename: A
authors.initials: A
authors.lastname: Fujioka
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: A
authors.initials: A
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Wierzba
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C064635:TAT 59; D004958:Estradiol