A NEW TRIPHENYLETHYLENE DERIVATIVE, TAT-59, HORMONE RECEPTORS, INSULIN-LIKE GROWTH-FACTOR-1, AND GROWTH SUPPRESSION OF HORMONE-DEPENDENT MCF-7 TUMORS IN ATHYMIC MICE

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 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 (E(2))-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 E(2) alone group. These results show the pronounced antiestrogenic action of TAT-59 on hormone-dependent MCF-7 tumors in athymic mice.