The preclinical development of bicalutamide: Pharmacodynamics and mechanism of action
The preclinical development of bicalutamide: Pharmacodynamics and mechanism of action
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DOI：
10.1016/s0090-4295(96)80003-3
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发表时间：
1996-01-01
期刊：
影响因子：
2.1
通讯作者：
Tucker, H
中科院分区：
文献类型：
--
作者：
Furr, BJA;Tucker, H
目标.描述比卡鲁胺的临床前开发并阐明其药效学和作用机制。比卡鲁胺是从一系列与氟替卡松相关的非甾体化合物中开发出来的，这些化合物显示出从完全雄激素激动剂到纯抗雄激素的一系列药理活性，包括促孕和抗孕特性。比卡鲁胺是一种与大鼠、犬和人前列腺结合的纯抗雄激素药物;与天然配体5 α-二氢睾酮相比，其亲和力较低，但比卡鲁胺对大鼠雄激素受体的亲和力约为羟基氟替卡松（氟替卡松的活性代谢产物）的4倍。比卡鲁胺还与LNCaP人前列腺肿瘤和Shionogi S115小鼠乳腺肿瘤细胞系中发现的雄激素受体结合，以及与转染到CV-1和HeLa细胞中的雄激素受体结合。在所有情况下，比卡鲁胺的作用都是作为一种纯抗雄激素，抑制雄激素刺激的基因表达和细胞生长。对LNCaP细胞系的研究特别令人感兴趣，因为这些细胞含有突变的雄激素受体（密码子868，Thr -> Ala），其与其他抗雄激素（醋酸环丙孕酮和氟氯孕酮）表现出特异性：这两种抗雄激素在该细胞系中均作为激动剂并刺激增殖。体内研究表明，比卡鲁胺在大鼠中是一种有效的抗雄激素。在每日接受丙酸睾酮给药的未成熟去势雄性大鼠中，比卡鲁胺在低至0.25 mg/kg的经口给药剂量下可显著抑制副性器官（腹侧前列腺和精囊）生长;在本试验中，比卡鲁胺的活性高于氟氯噻嗪或醋酸环丙孕酮。在成熟雄性大鼠中，每日经口给予比卡鲁胺可导致腹侧前列腺和精囊重量呈剂量相关性降低：在本试验中，比卡鲁胺的效力约为氟替卡松的5倍。与氟氯噻嗪不同，氟氯噻嗪由于中枢抑制雄激素对下丘脑-垂体-睾丸轴的负反馈作用，导致血清促黄体生成素（LH）和睾酮剂量相关性显著增加，比卡鲁胺对血清LH和睾酮几乎没有影响;即，它是外周选择性的。大鼠中比卡鲁胺的外周选择性不是由于前列腺与下丘脑或垂体受体之间的差异，因为比卡鲁胺在体外逆转了睾酮对下丘脑切片中促黄体生成激素释放激素（LHRH）分泌的抑制作用，并且在对LHRH给药后促垂体分泌LH的敏感性方面与氟氯噻嗪一样有效。现已证明，比卡鲁胺的外周选择性是由于通过血脑屏障的渗透性较差所致：[H-3]比卡鲁胺的组织分布研究表明，尽管它集中在代谢和分泌器官以及前列腺、垂体和精囊中，但在下丘脑和中枢神经系统（CNS）中的水平远低于血液中的水平。事实上，在中枢神经系统中发现的水平很可能反映了血液污染的水平。在犬中，比卡鲁胺具有极强的效力，可引起剂量相关的前列腺和附睾萎缩;口服艾德（50）为0.1 mg/kg，在该种属中，比卡鲁胺的效力约为氟氯噻嗪的50倍，也比甾体抗雄激素WIN 49596和5 α-还原酶抑制剂MK-906更有效。即使在活性剂量的实质性倍数（高达100 mg/kg经口给药）下，比卡鲁胺也未能增加血清睾酮，因此在犬中也具有外周选择性。磁共振成像研究表明，比卡鲁胺也是一种有效的抗雄激素的猴子; 1和5毫克/千克的口服剂量使精囊和腹侧前列腺的大小显著减小。在25毫克/千克的每日口服剂量下，比卡鲁胺对Dunning R3227 H可移植大鼠前列腺肿瘤的生长有非常显著的抑制作用，这与手术去势或用LHRH激动剂醋酸戈舍瑞林进行药物去势。在一项比较研究中，氟替卡松的效力和活性均低于比卡鲁胺。在所有这些临床前研究中，比卡鲁胺耐受性良好。在任何一般药理学试验中均无显著影响，但在犬中，长期给药时，当剂量>25倍于前列腺萎缩的艾德（50）值时，可引起心率小幅增加和PR间期缩短。由于在慢性毒性研究中检查心脏组织学时，既没有心脏功能受损，也没有病理学观察结果，因此可以得出结论，这种特异质结果没有毒理学后果。在经典内分泌试验中，比卡鲁胺被证明是一种纯抗雄激素药物，特别是不具有雌激素或非雌激素、孕激素或抗孕激素、糖皮质激素或抗糖皮质激素、盐皮质激素或抗盐皮质激素活性。比卡鲁胺也未显示出雄激素活性，并且不抑制类固醇5 α-还原酶。
Objectives. To describe the preclinical development of bicalutamide and clarify its pharmacodynamics and mechanism of action. Bicalutamide was developed from a series of nonsteroidal compounds related to flutamide that showed a range of pharmacologic activity from full androgen agonist to pure antiandrogen, including progestational and antiprogestational properties.Methods and Results. Bicalutamide is a pure antiandrogen that binds to rat, dog, and human prostate; the affinity compared with the natural ligand 5 alpha-dihydrotestosterone is low, but bicalutamide has an affinity for the rat androgen receptor approximately four times higher than hydroxyflutamide, the active metabolite of flutamide. Bicalutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, bicalutamide behaves as a pure antiandrogen and inhibits gene expression and cell growth stimulated by androgen. Studies with the LNCaP cell line are particularly interesting, as these cells contain a mutated androgen receptor (codon 868, Thr --> Ala), which behaves idiosyncratically with other antiandrogens (cyproterone acetate and flutamide): both these antiandrogens act as agonists in this cell line and stimulate proliferation. Studies in vivo show that bicalutamide is a potent antiandrogen in the rat. In immature, castrated male rats treated daily with testosterone propionate, bicalutamide produces a profound inhibition of accessory sex organ (ventral prostate and seminal vesicles) growth at oral doses as low as 0.25 mg/kg; it is more active in this test than flutamide or cyproterone acetate. In mature male rats, daily oral doses of bicalutamide produce a dose-related reduction in weights of the ventral prostate glands and seminal vesicles: in this test, bicalutamide is around five times as potent as flutamide. In contrast to flutamide, which produces dose-related, marked increases in serum luteinizing hormone (LH) and testosterone as a consequence of the central inhibition of the negative feedback effects of androgens on the hypothalamic-pituitary-testes axis, bicalutamide has little effect on serum LH and testosterone; i.e., it is peripherally selective. The peripheral selectivity of bicalutamide in the rat is not due to differences between the prostate versus hypothalamic or pituitary receptors, as bicalutamide reverses the suppressive effect of testosterone on luteinizing hormone-releasing hormone (LHRH) secretion from hypothalamic slices in vitro and is as effective as flutamide at sensitizing the pituitary gland to secrete LH in response to administered LHRH. The peripheral selectivity of bicalutamide has now been shown to be due to poor penetration across the blood-brain barrier: tissue distribution studies with [H-3]bicalutamide show that although it is concentrated in the organs of metabolism and secretion as well as in the prostate, the pituitary glands, and the seminal vesicles, levels in the hypothalamus and the central nervous system (CNS) are much lower than in blood. Indeed, it is probable that levels found in the CNS reflect levels of blood contamination. In dogs, bicalutamide has exquisite potency and causes dose-related atrophy of the prostate gland and epididymides; with an oral ED(50) of 0.1 mg/kg, it is around 50 times as potent as flutamide in this species and also more potent than the steroidal antiandrogen WIN49596 and the 5 alpha-reductase inhibitor MK-906. Even at substantial multiples of the active dose (up to 100 mg/kg orally), bicalutamide failed to increase serum testosterone, so it is also peripherally selective in the dog. Magnetic resonance imaging studies have shown that bicalutamide is also a potent antiandrogen in the monkey; oral doses of 1 and 5 mg/kg produced significant reductions in seminal vesicle and ventral prostate size.At a daily oral dose of 25 mg/kg, bicalutamide effected a highly significant reduction in growth of Dunning R3227H transplantable rat prostate tumors that was equivalent to that achieved by either surgical castration or medical castration with the LHRH agonist goserelin acetate. In a comparative study, flutamide was shown to be both less potent and less active than bicalutamide. In all these preclinical studies, bicalutamide was well tolerated. It had no significant effects in any general pharmacology tests except in the dog, in which, on chronic administration, it caused a small increase in heart rate and a reduction in PR interval at doses of >25 times the ED(50) value for prostate atrophy. Because there was neither impairment of cardiac function nor pathologic observations when cardiac histology was examined in chronic toxicity studies, it is concluded that this idiosyncratic finding is of no toxicologic consequence.Conclusions. Bicalutamide was shown to be a pure antiandrogen and specifically did not possess estrogenic or anestrogenic, progestational or antiprogestational, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid activity in classic endocrine tests. Bicalutamide also showed no androgenic activity and did not inhibit steroid 5 alpha-reductase.