Lønning P E, Kvinnsland S
Department of Therapeutic Oncology and Radiophysics, University of Bergen.
Drugs. 1988 Jun;35(6):685-710. doi: 10.2165/00003495-198835060-00005.
During the last decade aminoglutethimide has been recognised as a valuable alternative in endocrine therapy for advanced breast cancer. Although some side effects do occur, most often these are initial effects which subside within a few weeks, and cessation of therapy is not usually indicated. Aminoglutethimide was originally introduced as an inhibitor of steroidogenesis in the adrenal cortex. It was soon recognised, however, that inhibition of the non-glandular aromatase, blocking the conversion of androgenic prohormones to oestrogens, was more important, resulting in decreased blood levels of oestrogens. In this review the role of aromatase inhibition as the only important aspect of the mechanism of action of aminoglutethimide is challenged. Evidence has accumulated during the last few years that aminoglutethimide is a most potent inducer of microsomal enzymes. In addition to the pharmacological implications this has (suggesting important interactions), it also points to the possibility that levels of oestrogens are decreased due to accelerated metabolism of these hormones. Based on new experimental data, and also clinical work with alternative aromatase inhibitors, it appears that the antitumour activity of aminoglutethimide may be due to both aromatase inhibition and accelerated metabolism of oestrogens. This seriously challenges the importance of aromatase inhibition alone as a strategy in endocrine therapy of breast cancer, and furthermore suggests that accelerated metabolism of key hormones is an alternative strategy to be explored.
在过去十年中，氨鲁米特已被公认为晚期乳腺癌内分泌治疗中的一种有价值的替代药物。尽管确实会出现一些副作用，但大多数往往是初期效应，会在几周内消退，通常并不需要停止治疗。氨鲁米特最初作为肾上腺皮质类固醇生成的抑制剂被引入。然而，很快人们就认识到，抑制非腺体芳香化酶，阻断雄激素前体激素向雌激素的转化更为重要，这会导致血液中雌激素水平降低。在这篇综述中，芳香化酶抑制作为氨鲁米特作用机制的唯一重要方面这一观点受到了挑战。在过去几年里积累的证据表明，氨鲁米特是微粒体酶的一种非常有效的诱导剂。除了其药理学意义（提示重要的相互作用）外，这也指出了雌激素水平因这些激素代谢加速而降低的可能性。基于新的实验数据以及使用替代芳香化酶抑制剂的临床研究，氨鲁米特的抗肿瘤活性似乎可能是由于芳香化酶抑制和雌激素代谢加速共同作用的结果。这严重挑战了仅将芳香化酶抑制作为乳腺癌内分泌治疗策略的重要性，并且进一步表明关键激素代谢加速是一个有待探索的替代策略。
