Auvray P, Bichat F, Genne P
Oncodesign Biotechnology, Parc technologique de la Toison-d'Or, 28, rue de Broglie, 21000 Dijon, France.
Bull Cancer. 2000 Dec;87 Spec No:7-22.
Aromatase is an enzymatic complex responsible for the conversion of androgens into estrogens; these hormones are important in development, reproduction, but also in the growth of estrogen-dependent cancer. This enzyme is present in 60-70% of the breast cancer. The aromatase inhibitors are important drugs in the breast cancer treatment of postmenopausal women. In order to study their in vivo activity, animal models have been developed, e.g. rat with tumour induced by 7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice with aromatase transfected MCF-7 xenograft. In this review, we were interested in preclinical results obtained with both classes: steroidal and nonsteroidal inhibitors. The former group, as substrate analogs formestane or exemestane, are irreversible, selective and long-lasting inhibitors of aromatase. The nonsteroidal molecules, such as letrozole or anastrozole, are reversible inhibitors with high affinity. Finally, knowledge of the enzyme active site, with molecular modeling and site-directed mutagenesis, could be useful to develop new inhibitor families, more specific and potent in vivo.
芳香化酶是一种负责将雄激素转化为雌激素的酶复合物；这些激素在发育、生殖中很重要，在雌激素依赖性癌症的生长中也很重要。这种酶存在于60%至70%的乳腺癌中。芳香化酶抑制剂是绝经后女性乳腺癌治疗中的重要药物。为了研究它们的体内活性，已经开发了动物模型，例如用7,12-二甲基苯并[a]蒽诱导肿瘤的大鼠、用孕马血清促性腺激素预处理的未成熟大鼠或转染了芳香化酶的MCF-7异种移植的无胸腺裸鼠。在这篇综述中，我们关注了这两类药物（甾体类和非甾体类抑制剂）的临床前研究结果。前一组，如作为底物类似物的福美坦或依西美坦，是不可逆、选择性且长效的芳香化酶抑制剂。非甾体类分子，如来曲唑或阿那曲唑，是具有高亲和力的可逆抑制剂。最后，通过分子建模和定点诱变了解酶的活性位点，可能有助于开发新的抑制剂家族，使其在体内更具特异性和效力。
