Investigation of combined antiandrogens with LH-RH analogue for prostate cancer

促黄体生成素释放激素类似物(LH-RH)是前列腺癌去势治疗的有效替代药物。首次注射促黄体生成素-促性腺激素可引起一过性血清睾酮升高(T峰)，这可能导致疾病的进展，即所谓的“发作现象”。我们在1993年对抗雄激素与促黄体生成素受体联合治疗的初步研究表明，对T峰无抑制作用。这可能与抗雄激素剂量小，抗雄激素对下丘脑-垂体系统负反馈作用弱有关。1994年，为了确定抗雄激素预防“发作”的适当时间和剂量，在15周龄的大鼠上研究了两种类固醇化合物醋酸氯地酮17-acetoxy-6-chloro-2-oxa-4，6-pregnadiene-3，20-dione(TZP-4238)和一种非类固醇化合物氟他胺(FL)的剂量增加。抗雄激素灌胃0天或7天后，皮下注射1 mg/kg促黄体生成素受体。注射促黄体生成素后2小时测定血清T，3天后取前列腺组织行增殖细胞核抗原染色。结果表明：1)单次注射促黄体生成素受体可增加血清T、前列腺重量和标记指数(L.I.)；PCNA2)类固醇抗雄激素对T峰无抑制作用，对前列腺细胞生长有微弱抑制作用。3)非甾体类抗雄激素对T峰无抑制作用，且随用药时间的延长和剂量的增加而增强。而FL对细胞生长有明显的抑制作用。虽然这些结果不能为预防T峰建立合适的治疗方案，但建议在应用上述类固醇抗雄激素的同时，在注射LHRH时同时给予非类固醇类激素。

Lutenizing hormone-releasing hormone analogue (LH-RH) is useful alternative for castration in the treatment of prostate cancer. A initial injection of LH-RH causes transient increase of serum testosterone (T surge), which may cause progression of the disease, so called "flare up phenomenon". Our preliminary study in 1993 on combined treatment of antiandrogens with LH-RH had shown no inhibitory effect in T surge. This was probably because of small dosage and weak negative feed back to hypothalamus pituitary system of antiandrogens. In 1994, to determine adequate time and dosage of antiandrogens for preventing "flare up", increased doses of two steroidal compound, chlormadinone acetate, 17-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione (TZP-4238) and a non-steroidal one, flutamide (FL) were investigated in 15 week-old Wistar rats. Antiandrogens were given by gavage for 0 or 7 days before injection of 1mg/kg of LH-RH subcutaneously. Serum T was measured after 2 hours of LH-RH injection and prostate was resected for PCNA staining after 3 days. As results, 1)A single injection of LH-RH increased serum T,prostate weight and labeling index (L.I.) of PCNA.2)Steroidal antiandrogens showed no inhibition of T surge and weak suppression of prostate cell growth. 3)Non-steroidal antiandrogen didn't inhibit T surge, which intensified it in the longer duration and the larger dosage. But FL achieved significant suppression of the cell growth. Although these results can't establish proper regimen for prevention of T surge, it is suggested that foregoing steroidal antiandrogens should be followed with simultaneous administration of non-steroidal one at LH-RH injection.