Abstract | PURPOSE: 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: 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.
|
Authors | T Toko, J Shibata, M Nukatsuka, Y Yamada |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 39
Issue 5
Pg. 390-8
( 1997)
ISSN: 0344-5704 [Print] Germany |
PMID | 9054952
(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
|