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Estrogen agonistic/antagonistic effects of miproxifene phosphate (TAT-59)

AbstractPURPOSE:
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.
AuthorsJ Shibata, T Toko, H Saito, A E Lykkesfeldt, A Fujioka, K Sato, A Hashimoto, K Wierzba, Y Yamada
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 45 Issue 2 Pg. 133-41 ( 2000) ISSN: 0344-5704 [Print] Germany
PMID10663628 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents, Hormonal
  • Estrogen Antagonists
  • Receptors, Estrogen
  • Tamoxifen
  • TAT 59
  • Estradiol
Topics
  • Animals
  • Antineoplastic Agents, Hormonal (pharmacology)
  • Breast Neoplasms (pathology)
  • Cell Division (drug effects)
  • Drug Screening Assays, Antitumor
  • Estradiol (pharmacology)
  • Estrogen Antagonists (pharmacology)
  • Female
  • Humans
  • Lipid Metabolism
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen (physiology)
  • Tamoxifen (analogs & derivatives, pharmacology)
  • Transplantation, Heterologous
  • Tumor Cells, Cultured (drug effects)

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