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

促黄体激素释放激素类似物（LH-RH）是去势治疗前列腺癌的有效替代药物。初始注射rh可引起血清睾酮的短暂性升高（T激增），这可能导致疾病的进展，即所谓的“突然发作现象”。我们在1993年对抗雄激素与rh - rh联合治疗的初步研究显示对T激增没有抑制作用。这可能与抗雄激素剂量小，对下丘脑-垂体系统的负反馈较弱有关。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Wistar大鼠中研究了两种甾体化合物（17-乙酰氧基-6-氯-2-氧-4,6-孕二烯-3,20-二酮（TZP-4238））和一种非甾体化合物氟他胺（FL）的增加剂量。抗雄激素灌胃0或7天，皮下注射1h - rh 1mg/kg。注射rh - 2小时后测定血清T， 3天后切除前列腺进行PCNA染色。结果表明：1)单次注射rh - rh可提高血清T、前列腺重量和pcna标记指数（L.I.）。2)甾体抗雄激素对T激增无抑制作用，对前列腺细胞生长的抑制作用较弱。3)非甾体抗雄激素对T浪涌无抑制作用，但随着用药时间的延长和剂量的增大，T浪涌会增强。但FL对细胞生长有明显的抑制作用。虽然这些结果不能建立预防T激增的适当方案，但建议在rh - rh注射时，应在使用上述甾体抗雄激素药物的同时使用非甾体抗雄激素药物。

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.