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.