Martel C, Provencher L, Li X, St Pierre A, Leblanc G, Gauthier S, Mérand Y, Labrie F
Laboratory of Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
J Steroid Biochem Mol Biol. 1998 Feb;64(3-4):199-205. doi: 10.1016/s0960-0760(97)00192-1.
Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.
他莫昔芬（TAM）是目前唯一可用于乳腺癌内分泌治疗的抗雌激素药物，它表现为雌激素作用的混合激动剂/拮抗剂，因此限制了其治疗潜力。我们报告了一系列新型非甾体抗雌激素与大鼠子宫雌激素受体的结合特性。通过竞争研究测定，前药EM - 800的活性代谢物EM - 652对雌激素受体的亲和力比17β - 雌二醇（E2）、ICI 182780和他莫昔芬的活性代谢物羟基他莫昔芬（OH - TAM）高7至11倍。在将[3H]E2从大鼠子宫雌激素受体上置换下来方面，EM - 652比ICI 164384和屈洛昔芬强20倍，而比托瑞米芬强400倍。另一方面，前药EM - 800和他莫昔芬对雌激素受体的亲和力分别比纯抗雌激素EM - 652低150倍和410倍。在浓度高达10000 nM时，除了在4000 nM时他莫昔芬导致标记的R5020有50%的置换外，未观察到EM - 652、EM - 800、TAM或OH - TAM与大鼠子宫孕激素受体有明显结合。在大鼠腹侧前列腺雄激素受体或大鼠子宫孕激素受体上未观察到EM - 652或EM - 800有明显结合。目前的数据证明了新型抗雌激素EM - 652对大鼠子宫雌激素受体具有高亲和力和特异性。抗雌激素EM - 652因此成为已知对雌激素受体亲和力最高的化合物。由于其独特的效力以及已在许多系统中证明的纯抗雌激素活性，这种抗雌激素很可能为女性乳腺癌、子宫癌和其他雌激素敏感性疾病的内分泌治疗带来重要进展。
