Wakeling A E, Dukes M, Bowler J
ICI Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Cancer Res. 1991 Aug 1;51(15):3867-73.
Previous studies from this laboratory have described a series of 7 alpha-alkylamide analogues of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compound, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10 )- triene-3,17 beta-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotrophic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% effective doses of 0.06 and 0.9 mg/kg, respectively). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, respectively, compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concentrations of 0.29 and 1.3 nM, respectively, were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% reduction of cell number under conditions where 4'-hydroxytamoxifen achieved a maximum of 50% inhibition. This increased efficacy was reflected by a greater reduction of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells. Sustained antiestrogenic effects, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.
本实验室之前的研究描述了一系列具有纯抗雌激素活性的雌二醇7α-烷基酰胺类似物，以ICI 164,384为代表。现已鉴定出一种新化合物，即7α-[9-(4,4,5,5,5-五氟戊基亚磺酰基)壬基]雌-1,3,5(10)-三烯-3,17β-二醇（ICI 182,780），其抗雌激素效力显著增强且保留了纯雌激素拮抗剂活性。ICI 182,780在未成熟大鼠中的抗子宫增殖效力比ICI 164,384高10倍以上（半数有效剂量分别为0.06和0.9 mg/kg）。体内效力的这种数量级增加在一定程度上也反映在雌激素受体的内在活性上。与雌二醇（1.0）相比，ICI 182,780和ICI 164,384的相对结合亲和力分别为0.89和0.19。同样，在MCF-7人乳腺癌细胞中，ICI 182,780的体外生长抑制效力超过了ICI 164,384，记录到的半数抑制浓度分别为0.29和1.3 nM。ICI 182,780比4'-羟基他莫昔芬更有效地抑制MCF-7生长，在4'-羟基他莫昔芬最大抑制率为50%的条件下，ICI 182,780使细胞数量减少了80%。与他莫昔芬处理的细胞相比，ICI 182,780处理的细胞培养物中参与DNA合成的细胞比例降低幅度更大，这反映了其疗效的提高。在大鼠和猪尾猴中，单次肌内注射油悬液形式的ICI 182,780后均出现了持续的抗雌激素作用。在体内，ICI 182,780对裸鼠中MCF-7和Br10人乳腺癌异种移植瘤具有抗肿瘤活性。单次注射ICI 182,780提供的抗肿瘤疗效与每日他莫昔芬治疗至少4周的疗效相当。ICI 182,780的特性表明这种纯抗雌激素是评估完全雌激素撤退在内分泌反应性人乳腺癌中的潜在治疗益处的主要候选药物。
