Barrie S E, Potter G A, Goddard P M, Haynes B P, Dowsett M, Jarman M
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, England.
J Steroid Biochem Mol Biol. 1994 Sep;50(5-6):267-73. doi: 10.1016/0960-0760(94)90131-7.
Medical or surgical castration for the treatment of prostatic cancers prevents androgen production by the testes, but not by the adrenals. Inhibition of the key enzyme for androgen biosynthesis, cytochrome P450(17) alpha, could prevent androgen production from both sources. The in vivo effects of 17-(3-pyridyl)androsta-5,16-dien-3 beta-ol (CB7598) and 17-(3-pyridyl)androsta-5,16-dien-3-one (CB7627), novel potent steroidal inhibitors of this enzyme, on WHT mice were compared with those of castration and two clinically active compounds, ketoconazole and flutamide. Flutamide and surgical castration caused significant reductions in the weights of the ventral prostate and seminal vesicles. CB7598, in its 3 beta-O-acetate form (CB7630), and CB7627 caused significant reductions in the weights of the ventral prostate, seminal vesicles, kidneys and testes when administered once daily for 2 weeks. Ketoconazole, given on the same schedule, caused no reductions. Plasma testosterone was reduced to < or = 0.1 nM by CB7630, despite a 3- to 4-fold increase in the plasma level of luteinizing hormone. Adrenal weights were unchanged following treatment with CB7630 or CB7627 but were markedly increased following ketoconazole, indicating no inhibition of corticosterone production by these steroidal compounds. These results indicate that CB7598, CB7630 or CB7627 may be useful in the treatment of hormone-dependent prostatic cancers.
采用药物或手术去势治疗前列腺癌可抑制睾丸产生雄激素，但肾上腺仍可产生雄激素。抑制雄激素生物合成的关键酶细胞色素P450(17)α，可同时阻止这两个来源的雄激素产生。将新型强效甾体类该酶抑制剂17-(3-吡啶基)雄甾-5,16-二烯-3β-醇（CB7598）和17-(3-吡啶基)雄甾-5,16-二烯-3-酮（CB7627）对WHT小鼠的体内作用，与去势及两种临床活性化合物酮康唑和氟他胺的作用进行了比较。氟他胺和手术去势使前列腺腹侧叶和精囊重量显著减轻。CB7598的3β-O-乙酸酯形式（CB7630）和CB7627连续2周每日给药一次，可使前列腺腹侧叶、精囊、肾脏和睾丸重量显著减轻。按相同给药方案给予酮康唑则无此作用。尽管黄体生成素血浆水平升高了3至4倍，但CB7630仍可使血浆睾酮降至≤0.1 nM。用CB7630或CB7627治疗后肾上腺重量未改变，但酮康唑治疗后肾上腺重量显著增加，表明这些甾体化合物不抑制皮质酮的产生。这些结果表明，CB7598、CB7630或CB7627可能对激素依赖性前列腺癌的治疗有用。
