ANTIESTROGENIC ACTIVITY OF DP-TAT-59, AN ACTIVE METABOLITE OF TAT-59 AGAINST HUMAN BREAST-CANCER

Purpose: The purpose of this study was to clarify the mechanism(s) of antiestrogenic action of DP-TAT-59 )-2-(4-isopropyl-phenyl)-1-butenyl) phenoxy)-N,N-di ethylamine), the main active metabolite of TAT-59. Met hods: Using: 4-OH-tamoxifen (a hydroxylated metabolite of tamoxifen) a s a reference compound, we examined the relationship between hormone-d ependent tumor cells and DP-TAT-59 and characterized estrogen receptor (ER) complexes with DP-TAT-59 using ion-exchange chromatography. Resu lts: DP-TAT-59 inhibited the in vitro proliferation of MCF-7 cells und er serum-free conditions at a lower concentration than did dr-OH-tamox ifen. The conditioned medium (CM) obtained from the culture supernatan t of MCF-7 cells in the presence of these antiestrogens suppressed the growth of ER-negative cell lines, but that from ER-negative human mam mary carcinoma MX-1 cells did not. The CM from DP-TAT-59-treated cells showed a higher growth-inhibitory potency against human mammary carci noma ZR-75-1 cells than did that from 4-OH-tamoxifen-treated cells. Th e 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 treate d 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 competitiv e binding of [H-3]-estradiol with these antiestrogens to ER was simila r, ER complexes with DP-TAT-59 showed a different elution profile by i on-exchange chromatography, indicating that DP-TAT-59 formed a differe nt complex with ER from either 4-OH-tamoxifen or estradiol. Conclusion : These findings suggest that at least a part of the growth suppressiv e 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 pro duction of growth inhibitory factors might be stimulated by ER complex es with antiestrogens rather than with estrogen.