Gaillard-Moguilewsky M
Centre de Recherches Roussel-Uclaf, Romainville, France.
Urology. 1991;37(2 Suppl):5-12. doi: 10.1016/0090-4295(91)80095-o.
Antiandrogens are compounds able to block the effect of androgens directly on their target cells by inhibiting their binding to the androgen receptor (AR). Two chemical classes of antiandrogens are presently on the market or in clinical trials: steroids (cyproterone, megestrol acetates), and nonsteroids (flutamide, nilutamide). Steroid antiandrogens interact not only with AR but also with progestin and glucocorticoid receptors and thus give rise to progestin and glucocorticoid effects. By contrast, nonsteroid antiandrogens interact only with AR and are thus devoid of other hormonal or antihormonal activities. Nilutamide does not need to be transformed into an active metabolite, unlike flutamide, and interacts with dog, rat, and human prostate AR in vitro. Its kinetics lead to a prolonged interaction with AR in vivo after administration to rats. In prostate cancer treatment, it is necessary to combine an antiandrogen to surgical or chemical (estrogens, LH-RH agonists) castration to obtain a complete suppression of androgens. The antiandrogen will block specifically, at the target site, the trophic effect of adrenal androgens left intact by castration, and the secretion of which can only be suppressed by treatments (adrenalectomy, aminoglutethimide, ketoconazole) that also suppress corticoid synthesis. We have shown that nilutamide counteracts the trophic effect, on the prostate of castrated rats, of adrenal androgens administered continuously (minipumps) at circulating levels similar to those recorded in castrated men. Nilutamide will also impede the flare-up effect of the testosterone increase induced by LH-RH agonists at the beginning of treatment. We have shown in the rat treated with buserelin that the increase in prostate weight observed during the initial days of treatment by the LH-RH agonist can be inhibited by a combined treatment with nilutamide. This combined treatment "nilutamide plus castration" has been tested in an experimental androgen-dependent cancer model, the Shionogi tumor. The administration of nilutamide to mice, castrated twenty-four hours before the inoculation of tumor cells, delayed the appearance of tumors and reduced their number. Finally, the absence of androgen effect and the antiandrogen activity of the product were also demonstrated in human tumor cells in culture (T-47 D cells) transfected with the MMTV androgen-dependent promoter coupled with the CAT reporter gene.
抗雄激素是一类能够通过抑制雄激素与雄激素受体（AR）结合，直接阻断雄激素对其靶细胞作用的化合物。目前有两类抗雄激素药物已上市或正处于临床试验阶段：甾体类（环丙孕酮、醋酸甲地孕酮）和非甾体类（氟他胺、尼鲁米特）。甾体类抗雄激素不仅与AR相互作用，还与孕激素和糖皮质激素受体相互作用，因此会产生孕激素和糖皮质激素效应。相比之下，非甾体类抗雄激素仅与AR相互作用，因此没有其他激素或抗激素活性。与氟他胺不同，尼鲁米特无需转化为活性代谢产物，并且在体外能与犬、大鼠和人类前列腺AR相互作用。其动力学特性使其在给大鼠给药后，能在体内与AR产生长时间的相互作用。在前列腺癌治疗中，有必要将抗雄激素与手术去势或化学去势（雌激素、促性腺激素释放激素激动剂）联合使用，以实现对雄激素的完全抑制。抗雄激素将在靶位点特异性阻断去势后仍保持完整的肾上腺雄激素的营养作用，而肾上腺雄激素的分泌只能通过同时抑制皮质激素合成的治疗方法（肾上腺切除术、氨鲁米特、酮康唑）来抑制。我们已经证明，尼鲁米特能抵消在与去势男性体内记录的循环水平相似的情况下，持续（通过微型泵）给予肾上腺雄激素对去势大鼠前列腺的营养作用。尼鲁米特还会抑制促性腺激素释放激素激动剂在治疗开始时诱导的睾酮升高所产生的flare-up效应。我们在接受布舍瑞林治疗的大鼠中发现，促性腺激素释放激素激动剂在治疗初期观察到的前列腺重量增加可通过与尼鲁米特联合治疗来抑制。这种“尼鲁米特加去势”的联合治疗已在一种实验性雄激素依赖性癌症模型——日本住友肿瘤中进行了测试。在接种肿瘤细胞前24小时去势的小鼠中给予尼鲁米特，可延迟肿瘤出现并减少肿瘤数量。最后，在转染了与CAT报告基因偶联的MMTV雄激素依赖性启动子的培养人肿瘤细胞（T-47 D细胞）中，也证明了该产品不存在雄激素效应和抗雄激素活性。
