Labrie F, Dupont A, Belanger A, Lefebvre F A, Raynaud J P
J Pharmacol. 1983;14 Suppl 3:117-35.
Following the studies of Huggins and colleagues in 1941, the hormonal treatment of prostatic cancer has been aimed at neutralizing the influence of testicular androgens through surgical castration or the administration of high doses of estrogens. These two approaches cause a temporary improvement in 60 to 70% of advanced prostatic cancer. However, castration is not always well accepted and high doses of estrogens are frequently accompanied by lethal cardiovascular side effects. Following our observation that treatment with LHRH agonists causes a blockage in the biosynthesis of testosterone by the testis accompanied by a marked reduction in prostatic weight in the rat, the possibility was opened for a new approach in the treatment of prostatic cancer. Fortunately, among all species studied, man is the most sensitive to the inhibitory effect of LHRH agonists on testicular androgen biosynthesis and near-medical castration can be easily achieved without secondary effects other than those related to low androgen levels. Following long-term studies in the rat which have shown that the inhibitory effect of LHRH agonists is markedly potentiated by simultaneous administration of a pure antiandrogen, a study using the LHRH agonist [D-Ser(TBU)6, des-Gly-NH2(10)] LHRH ethylamide (HOE-766) and the pure antiandrogen RU-23908 was performed in men with advanced prostatic cancer. The combined treatment with the LHRH agonist and the antiandrogen in 37 patients not previously treated caused a positive objective response in 97% of cases while, previously, partial hormonal treatment achieved through castration or high doses of estrogens caused a positive response in 60 to 70% of patients. The serum levels of prostatic acid phosphatase (PAP) were decreased to 40% of control as early as four days after starting combined hormonal therapy. By contrast, in patients previously treated with estrogens or castrated, complete neutralization of adrenal androgens by the antiandrogen led to a much lower rate of positive response ranging from 25 to 55%. In patients previously treated, there is thus a predominance of tumor cells insensitive to androgens. An additional important finding in this study is that the administration of the antiandrogen prevents the flare-up of the disease frequently observed when LHRH agonists are administered alone.(ABSTRACT TRUNCATED AT 400 WORDS)
继1941年哈金斯及其同事的研究之后，前列腺癌的激素治疗旨在通过手术去势或给予高剂量雌激素来中和睾丸雄激素的影响。这两种方法能使60%至70%的晚期前列腺癌患者暂时病情改善。然而，去势并不总是能被很好地接受，高剂量雌激素常常伴有致命的心血管副作用。在我们观察到用促性腺激素释放激素（LHRH）激动剂治疗会导致睾丸睾酮生物合成受阻并伴有大鼠前列腺重量显著减轻之后，为前列腺癌治疗开辟了一种新方法的可能性。幸运的是，在所有研究的物种中，人类对LHRH激动剂对睾丸雄激素生物合成的抑制作用最为敏感，几乎能达到药物去势的效果，且除了与低雄激素水平相关的影响外，没有其他副作用。在对大鼠进行长期研究表明同时给予一种纯抗雄激素药物能显著增强LHRH激动剂的抑制作用之后，一项针对晚期前列腺癌男性患者的研究使用了LHRH激动剂[D - Ser(TBU)6，des - Gly - NH2(10)]LHRH乙酰胺（HOE - 766）和纯抗雄激素药物RU - 23908。对37例未接受过治疗的患者联合使用LHRH激动剂和抗雄激素药物治疗，97%的病例出现了阳性客观反应，而此前通过去势或高剂量雌激素进行的部分激素治疗，只有60%至70%的患者出现阳性反应。联合激素治疗开始仅四天后，前列腺酸性磷酸酶（PAP）的血清水平就降至对照值的40%。相比之下，在先前接受过雌激素治疗或去势的患者中，抗雄激素药物完全中和肾上腺雄激素后，阳性反应率要低得多，在25%至55%之间。因此，在先前接受过治疗的患者中，存在大量对雄激素不敏感的肿瘤细胞。这项研究的另一个重要发现是，给予抗雄激素药物可防止单独使用LHRH激动剂时经常出现的病情突然加重。（摘要截取自400字）
