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[Antitumor activity of miproxifene phosphate (TAT-59) against human mammary carcinoma].

Abstract
DP-TAT-59, an active metabolite of miproxifene phosphate (TAT-59), showed a strong anti-proliferating activity against ER-positive human mammary carcinoma cell lines, MCF-7 and T-47D, in the presence of 1 nM of estradiol. The ED50 value of DP-TAT-59 for each cell line was 30-fold lower than that of tamoxifen. TAT-59 suppressed the growth of mammary carcinoma, MCF-7 and Br-10, xenografted into nude mouse at a dose of 5 mg/kg/day, which is equivalent to 20 mg/body of daily dose to the patients. TAT-59 inhibited the growth of tamoxifen-resistant breast cancer cell lines, R-27 and FST-1, but not tamoxifen, suggesting the possible efficacy of TAT-59 for tamoxifen-refractory patients. DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 detected in blood after oral administration in the patients, exhibited equal growth-inhibitory activity against human mammary tumor xenograft, meaning the antitumor activity of TAT-59 may equally depend on these two metabolites. In uterotrophic testing using both immature mice and ovariectomized rats, while the effective dose of TAT-59 was lower than that of tamoxifen, TAT-59 showed dose-dependent estrogenic activity against their uteri, similar to tamoxifen. These results suggested that TAT-59 had a stronger antagonistic activity against estrogen-dependent mammary tumor than tamoxifen. We expect that TAT-59 will become an effective therapeutic agent for patients with high estrogen levels in their blood, such as premenopausal women, and the patients with whom the tamoxifen modality failed.
AuthorsT Toko, H Saito, A Fujioka, M Nukatuka, K Sato, A Hashimoto, J Shibata, Y Yamada
JournalGan to kagaku ryoho. Cancer & chemotherapy (Gan To Kagaku Ryoho) Vol. 25 Issue 6 Pg. 829-38 (May 1998) ISSN: 0385-0684 [Print] Japan
PMID9617321 (Publication Type: English Abstract, Journal Article)
Chemical References
  • Antineoplastic Agents
  • Estrogen Antagonists
  • Estrogens
  • Tamoxifen
  • TAT 59
Topics
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Breast Neoplasms (drug therapy, pathology)
  • Cell Division (drug effects)
  • Estrogen Antagonists (pharmacology, therapeutic use)
  • Estrogens (blood)
  • Female
  • Humans
  • Mice
  • Mice, Inbred ICR
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms, Hormone-Dependent (drug therapy, pathology)
  • Rats
  • Tamoxifen (analogs & derivatives, pharmacology, therapeutic use)
  • Tumor Cells, Cultured (drug effects)

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