TAT-59 ((E)-4-[1-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- isopropyl)phenyl-1-butenyl]-phenyl-monophosphate) treatment was performed on
hormone-dependent MCF-7
tumors in athymic mice.
TAT-59 given at 1, 5, and 20 mg/kg inhibited the
estrogen-stimulated growth of MCF-7
tumors in athymic mice in a dose-dependent fashion. The most clear decrease in
tumor growth was shown in the
TAT-59 alone group, although it was not dramatic. Average serum concentrations of DP-
TAT-59((Z)-[1-[4-[2-(dimethylamino)- ethoxy]phenyl]-2-(4-isopropyl)phenyl-1-butenyl]-4-
hydroxybenzene) and DM-DP-TAT-59(desmethyl-DP-TAT-59), metabolites of
TAT-59, increased in a dose-dependent manner. Much higher levels of
DP-TAT-59 and DM-DP-TAT-59 were shown in
tumors (target tissues of
estrogen) as compared with muscles (nontarget tissues of
estrogen) or serum. A serum concentration of
DP-TAT-59 or DM-DP-TAT-59 corresponding to the physiologic levels of serum
estradiol in premenopausal women was sufficient to inhibit the
estrogen-stimulated growth of MCF-7
tumors in mice.
TAT-59 induced a dose-dependent increase in
estrogen receptor levels in the MCF-7
tumors. In contrast, it prevented the
estradiol (E2)-induced increase in
progesterone receptor levels in a dose-dependent manner.
Insulin-like growth factor 1 levels measured in the MCF-7
tumors significantly decreased in the
TAT-59 alone group and in the no treatment group as compared with the E2 alone group. These results show the pronounced antiestrogenic action of
TAT-59 on
hormone-dependent MCF-7
tumors in athymic mice.