Fadrozole (CGS 16949A) is a selective, non-steroidal aromatase inhibitor with an IC50 value of 4.5μM[1]. Fadrozole has been investigated as a treatment of hormone-responsive breast cancer (estrogen sensitive)[1]. Aromatase is an enzyme that plays a vital role in converting androgens (like testosterone) into estrogens (like estradiol). Fadrozole can be used to block aromatase and reduces the level of estrogens[2].
In vitro, prolactin-positive cells were extracted from male Wistar rats. By treating prolactin-positive cells with 1μM Fadrozole alone for 1, 3, 6 or 12 hours respectively, no statistically significant variations in the cellular area and proliferation rates were observed due to absent testosterone and minimal synthesized estradiol[3]. When treating cells with 1μM Fadrozole and 1μM testosterone, significantly decreased of the size of prolactin-positive cells as well as reduced percentage of proliferation rates were obtained from 3 to 12 hours treatment[3].
In vivo, Fadrozole (300μg/day) was inplantated with mini-osmotic pumps on day 14 of pregnancy Sprague–Dawley rats to reduce the level of estradiol-17 (E2)[4]. Fadrozole (1200μg; 4 days) resulted in a significant reduced E2 concentration and high level of androstenedione and testosterone in pregnant rats[4]. Fadrozole (1800μg; 6 days) led to a fourfold increased intrauterine pressure with significant smaller uterine tissue framework in pregnant rats[2,4]. Fadrozole caused fetal abnormalities in pregnant rats, where 20% of fetuses had head injuries while their weight did not differ from normal fetuses[4].
References:
[1] Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A. Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease. Journal of medicinal chemistry. 1991 Feb;34(2):725-36.
[2] Tiboni GM, Ponzano A. Fetal safety profile of aromatase inhibitors: Animal data. Reproductive Toxicology. 2016 Dec 1;66:84-92.
[3] Patil CN, Li W, Wang X. Local transformations of androgens into estradiol by aromatase P450 are involved in the regulation of prolactin and the proliferation of pituitary prolactin-positive cells. J Endocrinol. 2014;222(2):201–12. doi:10.1530/JOE-13-0579.
[4] Tamada H, Shimizu Y, Inaba T, Kawate N, Sawada T. The effects of the aromatase inhibitor fadrozole hydrochloride on fetuses and uteri in late pregnant rats. Journal of endocrinology. 2004 Feb 1;180(2):337-46.
Fadrozole (CGS 16949A)是一种选择性非甾体芳香酶抑制剂，IC50 值为4.5μM[1]。Fadrozole已被研究用于治疗激素反应性乳腺癌（雌激素敏感）[1]。芳香酶在将雄激素（如睾酮）转化为雌激素（如雌二醇）中有着关键的作用。Fadrozole可用于阻断芳香酶并降低雌激素水平[2]。
在体外研究中，从Wistar雄性大鼠中提取催乳素阳性细胞，单独使用1μM的Fadrozole分别孵育1，3 ，6和12小时。由于细胞缺乏睾酮和极少合成的雌二醇，未观察到显著的细胞面积和增值率变化[3]。当合并使用1μM的Fadrozole和1μM的睾酮时，在3至12小时细胞孵育期间，催乳素阳性细胞的细胞大小显著减小并伴有细胞增值率的下降[3]。
在体内研究中，在Sprague–Dawley妊娠大鼠第14天时利用微型渗透泵将Fadrozole（300μg/day）注入体内以降低雌二醇-17（E2）[4]。Fadrozole（1200μg； 4天）导致妊娠大E2的浓度显著降低，且雄烯二酮和睾酮水平升高[4]。Fadrozole（1800μg；6天）导致妊娠大鼠子宫内压增加四倍，子宫组织框架变小[2，4]。Fadrozole导致妊娠大鼠胎儿畸形，其中20% 的小鼠胎儿头部有损伤，但其体重与正常小鼠胎儿没有差异[4]。