Mahler C, Verhelst J, Denis L
Department of Endocrinology, A. Z. Middelheim, Antwerp, Belgium.
Cancer. 1993 Feb 1;71(3 Suppl):1068-73. doi: 10.1002/1097-0142(19930201)71:3+<1068::aid-cncr2820711427>3.0.co;2-5.
Ketoconazole, an imidazole derivative, is an orally active antifungal agent. In high doses (400 mg three times a day), it inhibits the biosynthesis of testicular and adrenal androgens and may therefore be useful for the treatment of hormone dependent diseases such as advanced prostatic cancer. Similarly, a new imidazole derivative, liarozole, was recently found to interfere with testicular and adrenal steroid biosynthesis in animals and healthy volunteers.
The therapeutic and endocrine effects of ketoconazole and liarozole in patients with disseminated prostatic cancer are discussed, including data from the literature and personal experience.
Using high-dose ketoconazole, medical castration with the expected clinical response was achieved easily in previously untreated patients in all clinical series (personal data include seven patients). In patients with prostatic cancer who had relapses after castration, few objective remissions were achieved. By contrast, long-lasting subjective remissions, especially pain relief, were seen in more than half of the patients (personal data include 20 patients). Gastrointestinal intolerance, which was the main side effect, severely limits the routine use of the drug. Recently, the authors studied the effect of liarozole on adrenal steroid production in castrated patients whose disease was progressive after first-line treatment. Unlike ketoconazole therapy, adrenal androgen and cortisol levels were not modified. A Phase I-II trial was then done in 44 patients with metastatic prostatic cancer in clinical relapse. In patients with measurable disease, objective responses, including tumoral volume reduction, occurred in approximatively 30%. A prostate specific antigen reduction of 50% or more was noted in approximatively 50% of patients. Pain relief occurred in most patients. Mucocutaneous side effects were observed in most patients--dryness of the skin and onychomalacia. Raised tissue retinoic acid levels suggested a possible pathway by which this drug might exert its cytotoxic effects.
Ketoconazole in high doses is effective in first-line and second-line therapy for advanced prostatic cancer, but gastrointestinal side effects limit its routine use. Liarozole is a new imidazole that is also effective in second-line therapy for prostatic cancer and has fewer side effects. Unlike ketoconazole, its effect is not mediated by inhibition of steroid biosynthesis.
酮康唑是一种咪唑衍生物，是一种口服有效的抗真菌药物。高剂量（每日三次，每次400毫克）时，它可抑制睾丸和肾上腺雄激素的生物合成，因此可能对治疗激素依赖性疾病如晚期前列腺癌有用。同样，一种新的咪唑衍生物来曲唑，最近发现在动物和健康志愿者中可干扰睾丸和肾上腺类固醇的生物合成。
讨论了酮康唑和来曲唑在播散性前列腺癌患者中的治疗和内分泌作用，包括来自文献的数据和个人经验。
使用高剂量酮康唑，在所有临床系列中，先前未治疗的患者均轻松实现了预期临床反应的药物去势（个人数据包括7例患者）。在去势后复发的前列腺癌患者中，很少有客观缓解。相比之下，超过半数的患者出现了持久的主观缓解，尤其是疼痛缓解（个人数据包括20例患者）。胃肠道不耐受是主要副作用，严重限制了该药物的常规使用。最近，作者研究了来曲唑对一线治疗后疾病进展的去势患者肾上腺类固醇生成的影响。与酮康唑治疗不同，肾上腺雄激素和皮质醇水平未改变。然后对44例临床复发的转移性前列腺癌患者进行了I-II期试验。在可测量疾病的患者中，约30%出现了客观反应，包括肿瘤体积缩小。约50%的患者前列腺特异性抗原降低了50%或更多。大多数患者疼痛缓解。大多数患者出现了皮肤黏膜副作用——皮肤干燥和甲软化。组织视黄酸水平升高提示了该药物可能发挥细胞毒性作用的一条可能途径。
高剂量酮康唑对晚期前列腺癌的一线和二线治疗有效，但胃肠道副作用限制了其常规使用。来曲唑是一种新的咪唑，对前列腺癌的二线治疗也有效，且副作用较少。与酮康唑不同，其作用不是通过抑制类固醇生物合成介导的。
