Wakeling A E, Valcaccia B
J Endocrinol. 1983 Dec;99(3):455-64. doi: 10.1677/joe.0.0990455.
The relative oestrogenic and antioestrogenic activities in the immature rat uterus of the antioestrogens tamoxifen, trioxifene, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- less than 2-(1-pyrrolidinyl) ethoxyphenyl ketone (LY 117018) and 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- less than 2-(1-piperidinyl) ethoxyphenyl ketone (LY 139481) were compared. The efficacy of these compounds in inhibiting the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinomas was also measured. Tamoxifen and trioxifene were equipotent antioestrogens (ED50 = dose required to produce 50% reduction in oestradiol-stimulated uterine growth = 0.1 mg/kg); both compounds also demonstrated a maximal partial agonist (uterotrophic) effect of 40% that of oestradiol. LY 117018 and LY 139481 were less potent antioestrogens (ED50 = 0.7 and 0.25 mg/kg respectively) than tamoxifen but both compounds were also less oestrogenic (partial agonist activities 20 and 10% respectively compared with oestradiol). The differences in partial agonist activity were reflected by differences in maximum antioestrogenic effects. High doses of tamoxifen or trioxifene produced 60% inhibition of oestradiol-induced uterine growth whereas LY 117018 (80% inhibition) and LY 139481 (90% inhibition) were both more antioestrogenic because of their reduced partial agonist activity. In rats bearing DMBA-induced mammary tumours tamoxifen was the most effective inhibitor of tumour growth. In tamoxifen-treated animals only 7% (8/111) of hormone-dependent tumours showed progressive growth, compared to 60% in controls. The other antioestrogens were less effective; in trioxifene-treated animals 42% (18/43) of tumours continued to grow during treatment. Similarly, for LY 117018, 39% (14/36) and for LY 139481, 26% (10/38) of tumours showed progression. High doses of trioxifene and LY 117018 were markedly less efficacious than low doses. The increased separation between oestrogenic and antioestrogenic activity in the rat uterus, exemplified by LY 117018 and LY 139481 compared to tamoxifen and trioxifene, did not lead to increased antitumour efficacy.
比较了抗雌激素药物他莫昔芬、三苯氧胺、6-羟基-2-（对羟基苯基）-苯并[b]噻吩-3-基对＜2-（1-吡咯烷基）乙氧基苯基酮（LY 117018）和6-羟基-2-（对羟基苯基）-苯并[b]噻吩-3-基对＜2-（1-哌啶基）乙氧基苯基酮（LY 139481）在未成熟大鼠子宫中的相对雌激素活性和抗雌激素活性。还测定了这些化合物抑制7,12-二甲基苯并[a]蒽（DMBA）诱导的大鼠乳腺癌生长的效力。他莫昔芬和三苯氧胺是等效的抗雌激素药物（半数有效剂量ED50 =使雌二醇刺激的子宫生长减少50%所需的剂量 = 0.1 mg/kg）；这两种化合物还表现出最大部分激动剂（子宫营养）效应，为雌二醇的40%。LY 117018和LY 139481作为抗雌激素药物的效力低于他莫昔芬（ED50分别为0.7和0.25 mg/kg），但这两种化合物的雌激素活性也较低（与雌二醇相比，部分激动剂活性分别为20%和10%）。部分激动剂活性的差异反映在最大抗雌激素效应的差异上。高剂量的他莫昔芬或三苯氧胺可使雌二醇诱导的子宫生长抑制60%，而LY 117018（80%抑制）和LY 139481（90%抑制）因其较低的部分激动剂活性而具有更强的抗雌激素作用。在患有DMBA诱导的乳腺肿瘤的大鼠中，他莫昔芬是最有效的肿瘤生长抑制剂。在接受他莫昔芬治疗的动物中，只有7%（8/111）的激素依赖性肿瘤显示出进行性生长，而对照组为60%。其他抗雌激素药物效果较差；在接受三苯氧胺治疗的动物中，42%（18/43）的肿瘤在治疗期间继续生长。同样，对于LY 117018，39%（14/36）的肿瘤和对于LY 139481，26%（10/38）的肿瘤显示出进展。高剂量的三苯氧胺和LY 117018的疗效明显低于低剂量。与他莫昔芬和三苯氧胺相比，以LY 117018和LY 139481为例，大鼠子宫中雌激素活性和抗雌激素活性之间差异的增加并未导致抗肿瘤疗效的提高。
