The pharmacological actions of antiprogestins in uterine fibroids

抑制/调节孕酮受体(PR)转录活性的治疗作用 子宫肌瘤已经在这种疾病的临床前模型和几个模型中得到了很好的验证。 权威的临床研究。事实上，抗孕激素和选择性孕激素受体 调节剂(SPRM)已被证明可以减少肌瘤体积，控制出血和减少盆腔 压力。不幸的是，尽管肌瘤对这两类PR调节剂的急性反应 在疗效和一般副作用方面都是有利的，它们还会导致明显的 以子宫内膜腺和间质不同步为特征的子宫内膜改变 同样的腺体偶尔也会出现囊性扩张。尽管这些疾病的临床后果 意想不到的子宫内膜反应尚不清楚，它们已成为使用 抗孕激素和SPRM用于除短期治疗肌瘤外的所有药物。尽管这不太可能 需要长期研究来证明长期服用目前可用的 将进行抗孕激素/SPRM治疗，事实仍然是PR是最有效的药物靶点 对这种疾病的长期治疗。鉴于这一临床问题的重要性和未得到满足的需求 进行医疗干预，以减轻疾病的症状或改善 手术结果，我们认为PR调节器是一种基于机制的方法 Discovery可能会生产出具有更好的药学特性的药物。从我们对 核受体药理学的作用机制在过去的几年里，我们已经 了解到特定受体调节剂的相对激动剂/拮抗剂活性由以下因素决定 (A)配体对受体结构的影响，(B)辅因子的差异相互作用1 与不同构象的NR配体络合物，以及(C)相对表达水平和活性 靶细胞中的相关辅因子。我们已经利用这个概念开发了几个新的类 用于治疗癌症和其他疾病的不同功能的雄激素受体(AR)调节剂 雄激素病和一种新的抗雌激素药物目前正在对转移性癌症患者进行评估 乳腺癌。同样，我们建议评估特定的辅助激活因子和辅助抑制因子的作用(S 在子宫细胞模型中介导孕激素和抗孕激素的生物学反应 并将这些发现与肌瘤的生物学联系起来。这些研究将提供基本的见解 黄体酮和抗孕激素的分子作用机制可能会转化为 其他系统。然而，我们也预计，这次调查将导致发展和 确定有效治疗的新型抗孕激素/SPRM的新方法的验证 子宫肌瘤，但在子宫内膜中未表现出异常病理反应。

The therapeutic utility of inhibiting/modulating progesterone receptor (PR) transcriptional activity in uterine fibroids has been well validated both in preclinical models of this disease and in several definitive clinical studies. Indeed, both antiprogestins and Selective Progesterone Receptor Modulators (SPRMs) have been shown to reduce fibroid volume, control bleeding and reduce pelvic pressure. Unfortunately, whereas acute responses in fibroids to both classes of PR modulators have been favorable in terms of efficacy and general side effect profile, they also induce distinct endometrial changes that are characterized by asynchrony between endometrial glands and stroma with occasional cystic dilatation of these same glands. Although the clinical consequences of these unexpected endometrial responses are unclear, they have emerged as an impediment to the use of antiprogestins and SPRMs for all but short-term use as treatments for fibroids. Although it is unlikely that the long-term studies required to justify chronic administration of the currently available antiprogestins/SPRMs will be performed, the fact remains that PR is the best-validated drug target for extended treatment of this disease. Given the importance of this clinical problem and the unmet need for medical interventions that either mitigate the symptomatic presentation of the disease or improve surgical outcomes, it is our opinion that a mechanism-based approach toward PR modulator discovery may yield drugs with improved pharmaceutical profiles. From our studies of the mechanism of action of nuclear receptor (NR) pharmacology over the past few years, we have learned that the relative agonist/antagonist activity of specific receptor modulators is determined by (a) the impact of ligands on the structure of the receptor, (b) the differential interaction of cofactors1 with differently conformed NR-ligand complexes, and (c) the relative expression level and activity of relevant cofactors in target cells. We have exploited this concept to develop several new classes of functionally distinct androgen receptor (AR) modulators for the treatment of cancer and other androgenopathies and a new antiestrogen that is currently being evaluated in patients with metastatic breast cancer. Similarly, we propose to evaluate the role(s) of specific coactivators and corepressors in mediating the biological responses to progestins and antiprogestins in cellular models of uterine fibroids and relate these findings to the biology of fibroids. These studies will provide basic insights into the molecular mechanisms of action of progestins and antiprogestins that are likely to translate to other systems. However, we also anticipate that this investigation will lead to development and validation of new approaches with which to identify novel antiprogestins/SPRMs that effectively treat fibroids but which do not manifest abnormal pathological responses in the endometrium.