Aromatase inhibitors and hormone-dependent cancers.
Aromatase inhibitors and hormone-dependent cancers.
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芳香酶抑制剂和激素依赖性癌症。
DOI：
10.1016/0960-0760(90)90481-y
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发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Coombes,RC
中科院分区：
文献类型：
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作者：
Brodie,AM;Banks,PK;Inkster,SE;Dowsett,M;Coombes,RC
芳香酶（雌激素合成酶）存在于多种组织中。使用免疫细胞化学，我们最近在几种类型的人体组织的细胞区室中定位了这种酶。此外，我们发现 mRNA 位于与测试相同的结构中。由于性腺和外周形成的雌激素都会促进激素敏感性癌症的生长，因此我们开发了芳香酶抑制剂来阻止这种激素的合成。我们已经确定，4-羟基雄烯二酮 (4-OHA) 选择性抑制卵巢和外周组织中的芳香酶活性，并降低大鼠和非人类灵长类动物的血浆雌激素水平。 4-OHA 还被发现可以抑制受治疗动物的促性腺激素水平并降低雌激素和孕激素受体水平。这些作用的机制似乎与该化合物的弱雄激素活性有关。这些作用与芳香酶抑制一起可能导致协同反应，减少雌激素的产生和作用。在绝经后妇女中，雌激素主要来自外周。当绝经后乳腺癌患者每天口服或每周肠胃外服用不影响促性腺激素水平的 4-OHA 治疗时，血浆雌激素浓度显着降低。 100 名晚期乳腺癌患者中，34% 的患者对治疗出现完全或部分缓解，而 12% 的患者病情稳定。这些结果表明，4-OHA 对先前激素治疗复发的晚期疾病绝经后患者有益，而类固醇抑制剂可能对绝经前患者有价值。
Aromatase (estrogen synthetase) occurs in a variety of tissues. Using immunocytochemistry, we have recently located this enzyme in cellular compartments of several types of human tissue. Furthermore, we found the mRNA was located in the same structures where tested. As both gonadal and peripherally formed estrogen contribute to growth of hormone sensitive cancers, we have developed aromatase inhibitors to block synthesis of this hormone. We have determined that 4-hydroxyandrostenedione (4-OHA) selectively inhibits aromatase activity in ovarian and peripheral tissues and reduces plasma estrogen levels in rat and non-human primate species. 4-OHA was also found to inhibit gonadotropin levels and reduce estrogen and progesterone receptor levels in treated animals. The mechanism of these effects appear to be associated with the weak androgenic activity of the compound. These effects together with aromatase inhibition may result in a synergistic response reducing estrogen production and action. In postmenopausal women, estrogens are mainly of peripheral origin. When postmenopausal breast cancer patients were administered either daily oral or parenteral weekly treatment with 4-OHA at doses that did not affect their gonadotropin levels, plasma estrogen concentrations were significantly reduced. Complete or partial response to treatment occured in 34% of 100 patients with advanced breast cancer, while the disease was stabilized in 12%. These results indicate that 4-OHA is of benefit in postmenopausal patients with advanced disease who have relapsed from prior hormonal therapies, and that steroidal inhibitors may be of value in premenopausal patients.