Wei L L, Mangel W F, Katzenellenbogen B S
J Steroid Biochem. 1985 Dec;23(6A):875-81. doi: 10.1016/0022-4731(85)90042-1.
Tamoxifen aziridine (TA), an antiestrogen-based affinity label for the estrogen receptor, is highly selective and efficient in its covalent binding to the estrogen receptor (Katzenellenbogen et al., J. biol. Chem. 258 (1983) 3487-3495). Thus, it was of interest to investigate the biological character and potency of this compound and, in particular, to determine if the irreversible attachment of this tamoxifen-derived compound to the estrogen receptor would result in enhanced antiestrogenic properties or in unusual biological activity. The effect of tamoxifen aziridine and tamoxifen (Tam), the parent compound which is an antiestrogen that binds reversibly to the estrogen receptor, were compared with respect to their effects on uterine growth, growth of dimethylbenzanthracene (DMBA)-induced mammary tumors in rats, and proliferation and plasminogen activator activity of MCF-7 human breast cancer cells. In immature (day 20) rats, Tam and TA behaved as weak estrogen agonists and estrogen antagonists in that Tam or TA alone increased uterine weight to levels lower than that evoked by estradiol (E2), and both were able to suppress the stimulation of uterine weight evoked by E2. Administration of Tam and TA via Alzet minipumps (25 or 200 micrograms/rat/day) to mature rats bearing DMBA-induced mammary tumors resulted in marked regression and/or disappearance of most tumors. Uterine weights were also suppressed in these mature rats by Tam and TA. Tam was slightly more potent than TA in evoking tumor regression and in suppressing uterine weights in these in vivo studies. In MCF-7 human breast cancer cells in culture, Tam and TA suppressed cell proliferation and evoked no increase in plasminogen activator activity by themselves, while being very effective in preventing plasminogen activator activity stimulation by E2. Thus, TA displayed a bioactivity profile similar to that of Tam, the reversibly binding ligand, in vitro and in vivo. The covalent attachment of TA to the receptor does not, therefore, markedly alter the biological character or potency of the antiestrogen receptor complex.
他莫昔芬氮丙啶（TA）是一种基于抗雌激素的雌激素受体亲和标记物，在与雌激素受体的共价结合方面具有高度选择性和高效性（卡特泽伦博根等人，《生物化学杂志》258（1983）3487 - 3495）。因此，研究该化合物的生物学特性和效能，特别是确定这种源自他莫昔芬的化合物与雌激素受体的不可逆结合是否会导致增强的抗雌激素特性或异常的生物学活性，是很有意义的。将他莫昔芬氮丙啶和他莫昔芬（Tam）（一种可逆结合雌激素受体的抗雌激素母体化合物）对子宫生长、大鼠二甲基苯并蒽（DMBA）诱导的乳腺肿瘤生长以及MCF - 7人乳腺癌细胞增殖和纤溶酶原激活剂活性的影响进行了比较。在未成熟（第20天）大鼠中，Tam和TA表现为弱雌激素激动剂和雌激素拮抗剂，即单独使用Tam或TA会使子宫重量增加到低于雌二醇（E2）引起的水平，并且两者都能够抑制E2引起的子宫重量增加。通过Alzet微型泵（25或200微克/大鼠/天）给患有DMBA诱导的乳腺肿瘤的成熟大鼠施用Tam和TA，导致大多数肿瘤明显消退和/或消失。这些成熟大鼠的子宫重量也被Tam和TA抑制。在这些体内研究中，Tam在引起肿瘤消退和抑制子宫重量方面比TA稍强。在培养的MCF - 7人乳腺癌细胞中，Tam和TA抑制细胞增殖，自身不会引起纤溶酶原激活剂活性增加，同时在防止E2刺激纤溶酶原激活剂活性方面非常有效。因此，TA在体外和体内显示出与可逆结合配体Tam相似的生物活性谱。因此，TA与受体的共价结合不会显著改变抗雌激素受体复合物的生物学特性或效能。
