Iino Y, Takai Y, Ando T, Ohwada S, Yokoe T, Sugamata N, Takei H, Horiguchi J, Iijima K, Morishita Y
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
Cancer Chemother Pharmacol. 1994;34(5):372-6. doi: 10.1007/BF00685560.
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.
对无胸腺小鼠的激素依赖性MCF - 7肿瘤进行了TAT - 59（(E)-4-[1-[4-[2-(二甲氨基)乙氧基]-苯基]-2-(4-异丙基)phenyl-1-丁烯基]-苯基-单磷酸酯）治疗。以1、5和20 mg/kg的剂量给予TAT - 59可剂量依赖性地抑制无胸腺小鼠中雌激素刺激的MCF - 7肿瘤生长。单独使用TAT - 59组的肿瘤生长下降最为明显，尽管并不显著。TAT - 59的代谢产物DP - TAT - 59（(Z)-[1-[4-[2-(二甲氨基)-乙氧基]苯基]-2-(4-异丙基)phenyl-1-丁烯基]-4-羟基苯）和DM - DP - TAT - 59（去甲基-DP - TAT - 59）的平均血清浓度呈剂量依赖性增加。与肌肉（雌激素非靶组织）或血清相比，肿瘤（雌激素靶组织）中DP - TAT - 59和DM - DP - TAT - 59的水平要高得多。与绝经前女性血清雌二醇生理水平相对应的DP - TAT - 59或DM - DP - TAT - 59血清浓度足以抑制小鼠中雌激素刺激的MCF - 7肿瘤生长。TAT - 59可剂量依赖性地诱导MCF - 7肿瘤中雌激素受体水平升高。相反，它可剂量依赖性地阻止雌二醇（E2）诱导的孕酮受体水平升高。与单独使用E2组相比，单独使用TAT - 59组和未治疗组中MCF - 7肿瘤中测得的胰岛素样生长因子1水平显著降低。这些结果表明TAT - 59对无胸腺小鼠的激素依赖性MCF - 7肿瘤具有显著的抗雌激素作用。
