English H F, Santner S J, Levine H B, Santen R J
Cancer Res. 1986 Jan;46(1):38-42.
Ketoconazole is a well-tolerated, synthetic, imidazole derivative currently in widespread therapeutic use against mycotic infections. Recent evidence that it depresses testosterone synthesis in humans prompted us to investigate the effects in rats of its administration alone or in combination with the gonadotropin releasing hormone superagonist analogue leuprolide. Plasma luteinizing hormone, testosterone, and ketoconazole levels as well as ventral prostate weight and tumor growth in rats bearing the androgen-dependent Dunning R3327H model of prostate adenocarcinoma were measured. Doses of 30 mg/kg twice daily of ketoconazole alone depressed plasma testosterone levels by approximately 75% to a nadir of 0.47 +/- 0.08 (SE) ng/ml on day 20 (P less than 0.001 versus basal). This effect of ketoconazole was exerted directly at the testicular level since plasma luteinizing hormone levels were not suppressed. In response, ventral prostate weight declined and growth of the Dunning R3327H tumor was retarded to rates observed in castrate controls. Leuprolide alone lowered basal testosterone levels to 0.20 +/- 0.02 ng/ml after 35 days of daily administration but persistent androgen increments after each injection (acute-on-chronic effect) were observed (i.e., to 4.41 +/- 0.62 ng/ml). The addition of ketoconazole to leuprolide inhibited the acute-on-chronic rise in testosterone to 0.33 +/- .07 ng/ml and also lowered basal testosterone levels further to 0.11 +/- 0.01 on day 10 of combined administration. Ketoconazole also blunted the response to the first injection of leuprolide from a 3-h peak level of 8.74 +/- 0.53 to 4.17 +/- 0.80 with the 40 mg/kg dose. These results indicate that combining ketoconazole with leuprolide achieves greater suppression of testosterone than either agent alone. When such protocols are applied to humans with prostate cancer, more extensive effects may be expected because of the greater sensitivity of patients than of the rodent species to these agents.
酮康唑是一种耐受性良好的合成咪唑衍生物，目前广泛用于治疗真菌感染。最近有证据表明它会抑制人体睾酮的合成，这促使我们研究其单独给药或与促性腺激素释放激素超级激动剂类似物亮丙瑞林联合给药对大鼠的影响。我们测量了携带雄激素依赖性前列腺腺癌邓宁R3327H模型的大鼠的血浆促黄体生成素、睾酮和酮康唑水平，以及腹侧前列腺重量和肿瘤生长情况。单独使用酮康唑，剂量为30mg/kg，每日两次，在第20天时可使血浆睾酮水平降低约75%，降至最低点0.47±0.08（SE）ng/ml（与基础水平相比，P<0.001）。酮康唑的这种作用直接在睾丸水平发挥，因为血浆促黄体生成素水平未被抑制。作为反应，腹侧前列腺重量下降，邓宁R3327H肿瘤的生长速度减缓至去势对照组观察到的水平。单独使用亮丙瑞林，每日给药35天后，基础睾酮水平降至0.20±0.02 ng/ml，但每次注射后观察到持续的雄激素增加（急性加慢性效应）（即升至4.41±0.62 ng/ml）。在亮丙瑞林中加入酮康唑可将睾酮的急性加慢性升高抑制至0.33±0.07 ng/ml，并在联合给药第10天时将基础睾酮水平进一步降至0.11±0.01。酮康唑还将对首次注射亮丙瑞林的反应从3小时峰值水平8.74±0.53降至4.17±0.80（40mg/kg剂量）。这些结果表明，酮康唑与亮丙瑞林联合使用比单独使用任何一种药物都能更有效地抑制睾酮。当将此类方案应用于前列腺癌患者时，由于患者比啮齿动物对这些药物更敏感，可能会预期有更广泛的效果。
