Santen R J, Harvey H A
Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Endocr Relat Cancer. 1999 Mar;6(1):75-92. doi: 10.1677/erc.0.0060075.
Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.
芳香化酶是一种细胞色素P-450酶，可催化雄激素转化为雌激素，是绝经后女性雌激素合成的主要机制。我们回顾了一些近期的科学进展，这些进展揭示了芳香化酶在乳腺组织中的生物学意义、生理学、表达及调控。抑制芳香化酶这一雌激素生物合成的终末步骤，为治疗老年患者激素依赖性乳腺癌提供了一种方法。氨鲁米特是首个被广泛使用的芳香化酶抑制剂，但存在若干临床缺陷。新型药物选择性更高、效力更强、毒性更小且更易于在临床应用。本文回顾了支持使用强效口服竞争性芳香化酶抑制剂阿那曲唑、来曲唑和伏罗唑以及不可逆抑制剂4-羟基雄烯二酮和依西美坦的临床数据。效力更强的化合物可抑制外周及肿瘤内的芳香化酶。我们讨论了支持芳香化酶抑制剂与抗雌激素不存在交叉耐药这一观点的证据，并表明新型、效力更强的化合物可能在雌激素适应性超敏情况下的乳腺癌治疗中具有特殊应用。目前可用的芳香化酶抑制剂在治疗接受抗雌激素治疗失败的绝经后女性激素依赖性乳腺癌方面安全有效，现在应在使用孕激素类药物之前使用。有充分证据支持将这些化合物作为转移性乳腺癌的一线激素治疗以及老年患者辅助治疗方案的一部分进行试验，并且很可能用于乳腺癌的化学预防试验。
