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Antiestrogenic activity of DP-TAT-59, an active metabolite of TAT-59 against human breast cancer.

AbstractPURPOSE:
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.
CONCLUSION:
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.
AuthorsT Toko, J Shibata, M Nukatsuka, Y Yamada
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 39 Issue 5 Pg. 390-8 ( 1997) ISSN: 0344-5704 [Print] Germany
PMID9054952 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Culture Media, Conditioned
  • Estrogen Antagonists
  • Receptors, Estrogen
  • Transforming Growth Factor beta
  • Tamoxifen
  • TAT 59
  • 2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropylphenyl)-1-butenyl)phenoxy)-N,N-dimethylethylamine
  • afimoxifene
  • Estradiol
Topics
  • Binding, Competitive
  • Biological Transport
  • Breast Neoplasms
  • Cell Division (drug effects)
  • Chromatography, Ion Exchange
  • Culture Media, Conditioned
  • Estradiol (metabolism)
  • Estrogen Antagonists (metabolism, toxicity)
  • Female
  • Humans
  • Kinetics
  • Receptors, Estrogen (isolation & purification, metabolism)
  • Tamoxifen (analogs & derivatives, metabolism, toxicity)
  • Transforming Growth Factor beta (analysis, biosynthesis)
  • Tumor Cells, Cultured

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