Longcope C, Femino A, Johnston J O
Department of Obstetrics/Gynecology, University of Massachusetts Medical School, Worcester 01605.
Endocrinology. 1988 May;122(5):2007-11. doi: 10.1210/endo-122-5-2007.
The peripheral aromatization ([rho]BM) of androstenedione (A) and testosterone (T) was measured before and after administration of the aromatase inhibitor 10-(2 propynyl)estr-4-ene-3,17-dione (MDL-18,962) to five mature female baboons, Papio annubis. The measurements were made by infusing [3H]androstenedione/[14C]estrone or [3H]testosterone/[14C]estradiol for 3.5 h and collecting blood samples during the infusions and all urine for 96 h from the start of the infusion. Blood samples were analyzed for radioactivity as infused and product steroids, and the data were used to calculate MCRs. An aliquot of the pooled urine was analyzed for the glucuronides of estrone and estradiol and used to calculate the [rho]BM. MDL-18,962 was administered as a pulse in polyethylene glycol-400 (1-5 ml) either iv or via gastric tube 30 min before administration of the radiolabeled steroids. Control studies were done with and without polyethylene glycol-400 administration. When MDL-18,962 was given iv at 4 mg/kg, the aromatization of A was decreased 91.8 +/- 0.9% from the control value of 1.23 +/- 0.13% to 0.11 +/- 0.01%. At the same dose, aromatization of T was decreased 82.0 +/- 7.1%, from a control value of 0.20 +/- 0.03% to 0.037 +/- 0.018%. When MDL-18,962 was given iv at doses of 0.4, 0.1, 0.04, and 0.01 mg/kg, the values for aromatization of A were 0.16 +/- 0.03%, 0.18 +/- 0.06%, 0.37 +/- 11%, and 0.65 +/- 0.09%, respectively. The administration of MDL-18,962 via gastric tube at 4 mg/kg as a pulse decreased the aromatization of A from 1.35 +/- 0.06% to 0.43 +/- 0.12%, an inhibition of 67.2 +/- 10.7%. When administered via gastric tube daily for 5 days at 4 mg/kg, the aromatization of A fell from 1.35 +/- 0.06% to 0.063 +/- 0.003%, an inhibition of 84.4 +/- 0.5%. The MCRs of A and estrone were not altered by any dose of MDL-18,962 regardless of the mode of administration, but there was an increase in the MCRs of T and estradiol at the only dose (4 mg/kg, iv) at which these steroids were infused. The interconversions between the androgens and between the estrogens were not altered by the administration of MDL-18,962 at 4 mg/kg, iv. The enzyme-activated inhibitor MDL-18,962 is an effective inhibitor of [rho BM] in female baboons and could prove to be a useful therapeutic agent in treating estrogen-dependent breast cancer.
在给5只成年雌性阿拉伯狒狒（Papio annubis）静脉注射或经胃管给予芳香化酶抑制剂10-(2-丙炔基)雌-4-烯-3,17-二酮（MDL-18,962）之前和之后，测定雄烯二酮（A）和睾酮（T）的外周芳香化作用（[rho]BM）。通过输注[3H]雄烯二酮/[14C]雌酮或[3H]睾酮/[14C]雌二醇3.5小时，并在输注期间采集血样以及从输注开始后96小时收集所有尿液来进行测定。分析血样中的注入放射性和产物类固醇，并将数据用于计算代谢清除率（MCRs）。分析合并尿液的等分试样中的雌酮和雌二醇葡糖醛酸苷，并用于计算[rho]BM。在给予放射性标记类固醇前30分钟，将MDL-18,962以脉冲形式经静脉注射或经胃管给予，溶剂为聚乙二醇-400（1 - 5毫升）。进行了给予和不给予聚乙二醇-400的对照研究。当以4毫克/千克的剂量经静脉注射给予MDL-18,962时，A的芳香化作用从对照值1.23±0.13%降至0.11±0.01%，降低了91.8±0.9%。在相同剂量下，T的芳香化作用从对照值0.20±0.03%降至0.037±0.018%，降低了82.0±7.1%。当以0.4、0.1、0.04和0.01毫克/千克的剂量经静脉注射给予MDL-18,962时，A的芳香化作用值分别为0.16±0.03%、0.18±0.06%、0.37±11%和0.65±0.09%。以4毫克/千克的剂量经胃管脉冲给予MDL-18,962时，A的芳香化作用从1.35±0.06%降至0.43±0.12%，抑制率为67.2±10.7%。当以4毫克/千克的剂量经胃管每日给药5天时，A的芳香化作用从1.35±0.06%降至0.063±0.003%，抑制率为84.4±0.5%。无论给药方式如何，任何剂量的MDL-18,962均未改变A和雌酮的MCRs，但在唯一输注这些类固醇的剂量（4毫克/千克，静脉注射）下，T和雌二醇的MCRs有所增加。以4毫克/千克的剂量经静脉注射给予MDL-18,962不会改变雄激素之间以及雌激素之间的相互转化。酶激活抑制剂MDL-18,962是雌性狒狒中[rho BM]的有效抑制剂，可能被证明是治疗雌激素依赖性乳腺癌的有用治疗药物。
