Clinical and experimental evidence of inhibition of testosterone production by suramin
Clinical and experimental evidence of inhibition of testosterone production by suramin
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DOI：
10.1210/jc.81.6.2238
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发表时间：
1996-06-01
影响因子：
5.8
通讯作者：
Myers, CE
中科院分区：
文献类型：
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作者：
Danesi, R;LaRocca, RV;Myers, CE
在癌症患者、成年雄性大鼠、大鼠 Leydig 细胞和 NCI-H295 人肾上腺癌细胞中评估了苏拉明对睾酮产生的影响。在接受苏拉明治疗难治性癌症的 14 名患者中，血浆睾酮水平显着下降，其中 8 名患者的血浆 LH 和/或 FSH 水平升高超出正常范围。对 8 名患者进行了 hCG 刺激试验（5000 IU，肌肉注射），结果发现睾酮水平比基线值平均增加 2.1 倍。 1 名死于进行性疾病的患者在苏拉明治疗后进行了睾丸组织学检查；这表明生精小管萎缩，间质中的间质细胞减少。大鼠腹腔注射 18 mg/kg 苏拉明，每周两次，持续 8 周，血浆睾酮水平显着降低，而血浆 LH 和 FSH 水平没有显着变化。苏拉明治疗大鼠睾丸的细胞组织化学显示，与对照组相比，间质内 SP-羟基类固醇脱氢酶阳性细胞数量减少，光学显微镜检查显示精子发生严重受损。苏拉明抑制分离的大鼠 Leydig 细胞产生睾酮，以及从大鼠睾丸中提取的 3β-羟基类固醇脱氢酶将孕烯醇酮转化为黄体酮，50% 抑制浓度（IC50 值）分别为 108.2 和 87.5 μg/mL。此外，6天和12天后，苏拉明减少了NCI-H295肾上腺癌细胞培养基中睾酮的释放，IC50值分别为91.2和83.9μg/mL。这些数据为患者提供了第一个证据，表明苏拉明治疗可显着降低睾酮循环水平，这一结果也在实验模型中获得。
The effect of suramin on testosterone production was evaluated in cancer patients, adult male rats, rat Leydig cells, and NCI-H295 human adrenal cancer cells. Testosterone plasma levels markedly decreased in 14 patients receiving suramin as a therapy for refractory cancer, and in 8 of them, the plasma LH and/or FSH levels increased beyond the normal range. The hCG stimulation test (5000 IU, im) was performed in 8 patients and induced an average 2.1-fold increase in testosterone levels over baseline values. Testicular histology after suramin treatment was available in 1 patient who died of progressive disease; this revealed atrophy of seminiferous tubules and reduced Leydig cells in the interstitium. A significant reduction in plasma testosterone was also observed in rats given 18 mg/kg suramin, ip, twice weekly for 8 weeks, whereas plasma LH and FSH levels did not change significantly. Cytohistochemistry of testes from suramin-treated rats showed a reduced number of SP-hydroxysteroid dehydrogenase-positive cells within the interstitium compared to controls, and light microscopy revealed severe impairment of spermatogenesis. Suramin inhibited the production of testosterone by isolated rat Leydig cells as well as the conversion of pregnenolone to progesterone by the 3 beta-hydroxysteroid dehydrogenase enzyme extracted from rat testes, with 50% inhibitory concentrations (IC50 values) of 108.2 and 87.5 mu g/mL, respectively. Furthermore, suramin reduced the release of testosterone into the culture medium of NCI-H295 adrenal cancer cells with IC50 values of 91.2 and 83.9 mu g/mL, after 6 and 12 days, respectively. These data provide the first evidence in patients that suramin treatment produces a marked reduction in the circulating levels of testosterone, a result that was also obtained in experimental models.