Dowsett M, Cunningham D C, Stein R C, Evans S, Dehennin L, Hedley A, Coombes R C
Department of Biochemical Endocrinology, Royal Marsden Hospital, London.
Cancer Res. 1989 Mar 1;49(5):1306-12.
4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these plus a further 11 patients were then randomized to treatment with 250 or 500 mg i.m. every 2 weeks to determine the optimal dose for each route according to the suppression of serum estradiol levels. There was no significant difference between the 3 oral doses in their suppression of estradiol levels indicating that the maximum required p.o. dose of 4-OHA is probably 250 mg daily. Suppression by the parenteral dose of 250 mg every 2 weeks was marginally suboptimal but clinical considerations of response and tolerability indicate this as the optimal dose for i.m. injection. 4-OHA had no effect on serum levels of androstenedione, testosterone, or 5 alpha-dihydrotestosterone when given by either route but p.o. treatment with 4 doses of 250 mg daily reduced sex hormone-binding globulin levels by a mean of 34%. Serum levels of estrone as measured by gas chromatography-mass spectrometry were suppressed to approximately 40% of baseline by parenteral treatment. The half-life of 4-OHA p.o. was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection.
4-羟基雄烯二酮（CGP32349；4-OHA）通过胃肠外和口服途径对晚期绝经后乳腺癌具有临床疗效，这是由于其抑制芳香化酶并进而抑制血浆雌激素水平的结果。30名患者被随机分为三组，分别接受每日口服1次、2次和4次250mg 4-OHA的治疗，持续2周。然后，这30名患者中的29名以及另外11名患者被随机分为两组，分别接受每2周一次肌肉注射250mg或500mg 4-OHA的治疗，以根据血清雌二醇水平的抑制情况确定每种给药途径的最佳剂量。三种口服剂量在抑制雌二醇水平方面没有显著差异，这表明4-OHA的最大口服剂量可能为每日250mg。每2周一次肌肉注射250mg的剂量抑制效果略欠佳，但从反应和耐受性的临床考虑来看，这被认为是肌肉注射的最佳剂量。无论通过哪种途径给药，4-OHA对血清雄烯二酮、睾酮或5α-二氢睾酮水平均无影响，但每日口服4次250mg的治疗使性激素结合球蛋白水平平均降低了34%。通过气相色谱-质谱法测量，胃肠外治疗使血清雌酮水平降至基线水平的约40%。4-OHA口服后的半衰期约为3小时，而注射药物的表观半衰期在注射后的前4天快速清除后为5至10天。
