Santen R J
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
J Steroid Biochem Mol Biol. 1991;40(1-3):247-53. doi: 10.1016/0960-0760(91)90189-c.
The biological importance of aromatase rests in the concept that this is the rate-limiting enzyme involved in estrogen biosynthesis. Approx. one-third of human breast carcinomas depend upon estrogen for growth. Blockade of estrogen biosynthesis, then, provides an effective means of causing tumor regression in selected patients. The side effects and lack of specificity of the aromatase inhibitor, aminoglutethimide, provided the impetus toward development of nonsteroidal inhibitors of aromatase. Several compounds are currently being evaluated. Pyridoglutethimide is a derivative of aminoglutethimide which does not inhibit cholesterol side-chain cleavage and possesses no CNS sedative properties; the Ki for aromatase is 1100 nM, somewhat higher than for aminoglutethimide, 600 nM. CGS 16949A is a highly potent inhibitor of aromatase which is an imidazole derivative. This compound inhibits aromatase with a Ki of 0.19 nM whereas inhibition of C11-hydroxylase activity occurs at 10(-6) M. In clinical trials, this compound lowers plasma estrogen levels, blocks peripheral aromatization as documented by isotopic kinetic studies, and causes tumor regression. Phase III trials with this drug are now ongoing. Another agent, R76713, represents another highly potent and specific aromatase inhibitor with little toxicity in animal studies. The Ki for placental aromatase is 0.8 nM and this compound is approx. 500-fold more potent than aminoglutethimide. Phase I clinical studies in patients reveal a marked reduction in estrogen production. These compounds represent the most promising of a wide variety of agents currently being tested for their aromatase inhibitory properties.
芳香化酶的生物学重要性在于这样一个概念，即它是雌激素生物合成中的限速酶。大约三分之一的人类乳腺癌依赖雌激素生长。因此，阻断雌激素生物合成提供了一种使特定患者肿瘤消退的有效方法。芳香化酶抑制剂氨鲁米特的副作用和缺乏特异性推动了非甾体芳香化酶抑制剂的研发。目前正在评估几种化合物。吡啶鲁米特是氨鲁米特的衍生物，它不抑制胆固醇侧链裂解，也不具有中枢神经系统镇静特性；其对芳香化酶的抑制常数（Ki）为1100 nM，略高于氨鲁米特的600 nM。CGS 16949A是一种高效的芳香化酶抑制剂，是一种咪唑衍生物。该化合物抑制芳香化酶的Ki为0.19 nM，而对11β-羟化酶活性的抑制作用在10⁻⁶ M时出现。在临床试验中，该化合物可降低血浆雌激素水平，同位素动力学研究证明它能阻断外周芳香化作用，并导致肿瘤消退。目前正在进行该药物的III期试验。另一种药物R76713是另一种高效且特异性的芳香化酶抑制剂，在动物研究中几乎没有毒性。其对胎盘芳香化酶的Ki为0.8 nM，该化合物的效力约为氨鲁米特的500倍。对患者进行的I期临床研究显示雌激素生成显著减少。这些化合物是目前正在测试其芳香化酶抑制特性的众多药物中最有前景的。
