Brueggemeier Robert W
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Hormones and Cancer Program, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Semin Reprod Med. 2004 Feb;22(1):31-43. doi: 10.1055/s-2004-823025.
Estrogens are involved in numerous physiological processes and have crucial roles in certain disease states such as mammary carcinoma. Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in breast tissue, and the importance of intratumoral aromatase and local estrogen production is being unraveled. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. Competitive aromatase inhibitors are molecules that compete with the substrate androstenedione for noncovalent binding to the active site of the enzyme to decrease the amount of product formed. Steroidal inhibitors that have been developed to date build upon the basic androstenedione nucleus and incorporate chemical substituents at varying positions on the steroid. Nonsteroidal aromatase inhibitors can be divided into three classes: aminoglutethimide-like molecules, imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase inhibitors are steroidal inhibitors that mimic the substrate, are converted by the enzyme to a reactive intermediate, and result in the inactivation of aromatase. Both steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy for the treatment of breast cancer. The initial nonselective nature of nonsteroidal inhibitor aminoglutethimide has been greatly reduced in the later generations of inhibitors, anastrozole and letrozole. Mechanism-based steroidal inhibitors such as 4-hydroxyandrostenedione and exemestane produce potent aromatase inhibition in patients. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, are approved for clinical use in postmenopausal patients with advanced hormone-dependent breast cancer or in patients failing antiestrogen therapies. Several clinical studies of aromatase inhibitors are currently focusing on the use of these agents in the adjuvant setting for the treatment of early breast cancer.
雌激素参与众多生理过程，在某些疾病状态如乳腺癌中起着关键作用。雌二醇是最具活性的内源性雌激素，由细胞色素P450酶复合物芳香化酶从雄激素生物合成而来。芳香化酶存在于乳腺组织中，肿瘤内芳香化酶和局部雌激素产生的重要性正在被揭示。抑制芳香化酶是减少雌激素对雌激素依赖性乳腺癌生长刺激作用的重要方法。竞争性芳香化酶抑制剂是与底物雄烯二酮竞争非共价结合到酶活性位点以减少产物形成量的分子。迄今为止开发的甾体抑制剂基于基本的雄烯二酮核，并在甾体的不同位置引入化学取代基。非甾体芳香化酶抑制剂可分为三类：氨鲁米特样分子、咪唑/三唑衍生物和类黄酮类似物。基于机制的芳香化酶抑制剂是模拟底物的甾体抑制剂，被酶转化为反应性中间体，导致芳香化酶失活。甾体和非甾体芳香化酶抑制剂均已显示出治疗乳腺癌的临床疗效。非甾体抑制剂氨鲁米特最初的非选择性在后来的抑制剂阿那曲唑和来曲唑中已大大降低。基于机制的甾体抑制剂如4-羟基雄烯二酮和依西美坦在患者中产生强效的芳香化酶抑制作用。强效且选择性的第三代芳香化酶抑制剂阿那曲唑、来曲唑和依西美坦已被批准用于绝经后晚期激素依赖性乳腺癌患者或抗雌激素治疗失败的患者的临床治疗。目前，几项关于芳香化酶抑制剂的临床研究集中于这些药物在辅助治疗早期乳腺癌中的应用。
