Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance
Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance
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DOI：
10.1007/s10549-005-9037-3
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发表时间：
2005-01-01
影响因子：
3.8
通讯作者：
Pietras, RJ
中科院分区：
文献类型：
--
作者：
Dowsett, M;Nicholson, RI;Pietras, RJ
了解内分泌抵抗的潜在机制仍然是改善乳腺癌治疗的一个挑战。生长因子和雌激素受体（ER）信号通路在内分泌抵抗性乳腺癌中相互作用的发现为破坏ER阳性内分泌抵抗性肿瘤中的这些信号级联提供了理论基础。在绝经后女性中，可以使用氟维司群（“芙仕得”）靶向ER信号通路，这是一种新型ER拮抗剂，无激动剂作用。氟维司群结合、阻断并导致ER降解，最终完全消除雌激素敏感基因转录。这种独特的作用机制可能导致缺乏与其他内分泌药物的交叉耐药性。临床前研究证实了氟维司群抑制他莫昔芬耐药和他莫昔芬敏感的人乳腺癌细胞系生长的潜力。临床研究表明，氟维司群是既往内分泌治疗进展的绝经后晚期乳腺癌女性的有效治疗选择。此外，临床前研究表明，将氟维司群与生长因子靶向药物，如表皮生长因子受体（EGFR/HER 1）酪氨酸激酶抑制剂吉非替尼（IRESSA）或抗人HER 2单克隆抗体曲妥珠单抗（Herceptin）组合，可产生比任一药物单独使用更大的抗肿瘤活性。目前正在进行一系列临床试验，以确定生长因子靶向药物与氟维司群的组合是否会延迟内分泌抵抗的发生，从而为激素受体阳性晚期乳腺癌女性提供新的策略。
Understanding the underlying mechanisms responsible for endocrine resistance remains a challenge in improving the treatment of breast cancer. The discovery that growth factor and estrogen receptor (ER) signaling pathways interact in endocrine resistant breast cancer has provided a rationale for disrupting these signaling cascades in ER-positive, endocrine-resistant tumors. In postmenopausal women, the ER signaling pathway may be targeted using fulvestrant ('Faslodex'), a new type of ER antagonist with no agonist effects. Fulvestrant binds, blocks and causes degradation of the ER, culminating in complete abrogation of estrogen-sensitive gene transcription. This unique mechanism of action may result in a lack of cross-resistance with other endocrine agents. Preclinical studies have confirmed the potential of fulvestrant to inhibit the growth of tamoxifen-resistant, as well as tamoxifen-sensitive, human breast cancer cell lines. Clinical studies have demonstrated that fulvestrant is an effective treatment option in postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy. Furthermore, preclinical studies indicate that combining fulvestrant with growth factor targeted agents, such as the epidermal growth factor receptor (EGFR/HER1) tyrosine kinase inhibitor gefitinib (IRESSA) or the anti-human HER2 monoclonal antibody trastuzumab (Herceptin'), may result in greater anti-tumor activity than either agent alone. A range of clinical trials are now ongoing to determine whether the combination of growth factor-targeting agents with fulvestrant will delay the onset of endocrine resistance and so provide new strategy for women with hormone receptor-positive advanced breast cancer.