Hoffmann J, Sommer A
Research Laboratories of Schering AG, Müller Str. 178, 13342 Berlin, Germany.
J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):191-200. doi: 10.1016/j.jsbmb.2004.12.002. Epub 2005 Jan 28.
Surgical ovariectomy and orchiectomy, first proposed over a century ago, are effective in breast and prostate cancer therapy, respectively. Later, the discovery of steroid hormones and their nuclear receptors led to the concept that inhibition of steroid receptor function by an antagonist prevents tumour growth. While the first anti-hormones, cyproteroneacetate (CPA) and tamoxifen were found accidentally, deeper understanding of nuclear receptors as transcription factors enabled more rational, structure-activity based drug discovery. Results from a drug-finding program on pure anti-estrogens will be reported. These new steroidal anti-estrogens are highly active, pure ER-antagonists that lead to an efficient degradation of the estrogen receptor alpha (ERalpha) protein without any agonistic activity. Data obtained in preclinical tumour models in mice and rats showed a high potency in growth inhibition of ERalpha-positive breast cancer. In parallel, by comparing three independently generated anti-estrogen-resistant breast cancer cell lines, it was our intention to gain insight into the mechanisms of endocrine resistance which will allow to define new approaches for the treatment of endocrine-resistant breast cancer. Candidate proteins potentially involved in mechanisms of anti-estrogen-resistant growth of breast cancer cell lines were analyzed. ERalpha and progesterone receptor (PR) expressions were lost on the protein level in all three anti-estrogen-resistant cell lines, whereas binding of epidermal growth factor (EGF) and protein expression of epidermal growth factor receptor (EGFR) were increased. Loss of ERalpha expression may be linked to the acquisition of anti-estrogen resistance and enhanced expression of the EGFR and of members of the S100 family of Ca2+-binding proteins may contribute to the outgrowth of resistant cells. Furthermore, we describe the pharmacological development of a novel, highly potent progesterone receptor antagonist. In rat mammary tumour models, treatment with the PR antagonist completely suppressed the growth of established tumours and prevented the development of breast tumours. Advanced prostate cancer is effectively treated by androgen ablation. However, this therapy becomes inefficient although the androgen receptor (AR) is still functionally expressed. One novel strategy for the treatment of advanced prostate cancer could be the selective inhibition of AR protein expression by anti-sense oligonucleotides or small interfering RNA (siRNA) molecules. Down-regulation of the human AR caused significant inhibition of LNCaP prostate cancer growth in vivo. Taken together, many promising alternatives for endocrine therapy of breast and prostate cancer are arising.
外科卵巢切除术和睾丸切除术分别于一个多世纪前首次提出，在乳腺癌和前列腺癌治疗中均有效。后来，类固醇激素及其核受体的发现催生了这样一种概念，即拮抗剂抑制类固醇受体功能可阻止肿瘤生长。虽然最初的抗激素药物醋酸环丙孕酮（CPA）和他莫昔芬是偶然发现的，但对作为转录因子的核受体的更深入了解推动了基于结构活性的更合理药物研发。将报告一项关于纯抗雌激素药物研发项目的结果。这些新型甾体抗雌激素是高活性的纯雌激素受体拮抗剂，可导致雌激素受体α（ERα）蛋白有效降解且无任何激动活性。在小鼠和大鼠的临床前肿瘤模型中获得的数据显示，其对ERα阳性乳腺癌的生长抑制效力很高。同时，通过比较三种独立产生的抗雌激素耐药乳腺癌细胞系，我们旨在深入了解内分泌耐药机制，从而确定治疗内分泌耐药乳腺癌的新方法。分析了可能参与乳腺癌细胞系抗雌激素耐药生长机制的候选蛋白。在所有三种抗雌激素耐药细胞系中，ERα和孕激素受体（PR）的蛋白表达均缺失，而表皮生长因子（EGF）的结合及表皮生长因子受体（EGFR）的蛋白表达增加。ERα表达缺失可能与抗雌激素耐药的获得有关，而EGFR及S100钙结合蛋白家族成员的表达增强可能有助于耐药细胞的生长。此外，我们描述了一种新型高效孕激素受体拮抗剂的药理学研发情况。在大鼠乳腺肿瘤模型中，用该PR拮抗剂治疗可完全抑制已形成肿瘤的生长并预防乳腺肿瘤的发生。晚期前列腺癌可通过雄激素剥夺有效治疗。然而，尽管雄激素受体（AR）仍有功能表达，但这种治疗会变得无效。治疗晚期前列腺癌的一种新策略可能是通过反义寡核苷酸或小干扰RNA（siRNA）分子选择性抑制AR蛋白表达。人AR的下调在体内显著抑制了LNCaP前列腺癌的生长。综上所述，乳腺癌和前列腺癌内分泌治疗出现了许多有前景的替代方法。
