3RD ANNUAL WILLIAM-L-MCGUIRE-MEMORIAL-LECTURE - STUDIES ON THE ESTROGEN-RECEPTOR IN BREAST-CANCER - 20 YEARS AS A TARGET FOR THE TREATMENT AND PREVENTION OF CANCER
3RD ANNUAL WILLIAM-L-MCGUIRE-MEMORIAL-LECTURE - STUDIES ON THE ESTROGEN-RECEPTOR IN BREAST-CANCER - 20 YEARS AS A TARGET FOR THE TREATMENT AND PREVENTION OF CANCER
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DOI：
10.1007/bf00713399
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发表时间：
1995-01-01
影响因子：
3.8
通讯作者：
JORDAN, VC
中科院分区：
文献类型：
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作者：
JORDAN, VC
在1973年，McGuire和Chamness（In：O 'Malley BW and Means AR（eds）Receptors for Reproductive Hormones，Plenum Press）总结了他们关于动物和人类乳腺肿瘤中雌激素受体的工作，并在此过程中描述了治疗干预的靶点。当时没有临床上有用的抗雌激素，但随后开发的他莫昔芬用于乳腺癌治疗，彻底改变了治疗方法。长期辅助他莫昔芬辅助治疗（即超过一年）已被证明有效提高乳腺癌患者的生存率。此外，由于在他莫昔芬辅助治疗期间，对侧乳腺癌的发生率降低了40%，并且他莫昔芬保持了骨密度并减少了致命性心肌梗死，因此在美国、英国和意大利开始了临床试验，以测试他莫昔芬作为高危女性乳腺癌预防剂的价值。最初的关注，长期他莫昔芬导致子宫内膜癌已被放置在透视和分析的文献回顾。他莫昔芬仅使检测到子宫内膜癌的正常风险增加一倍（即每年每1,000名接受他莫昔芬治疗的妇女中有2人），并且这些病例中的80%是早期，预后良好的疾病。每年的妇科检查和教育是必不可少的，为患者提供放心。他莫昔芬的成功鼓励了新的抗雌激素药物的开发，以利用雌激素受体作为治疗靶点。屈洛昔芬和达特-59在对雌激素受体具有高亲和力方面模拟代谢物4-羟基他莫昔芬（Jordan等人，J Endocrinol 75：305，1977）。这些药物似乎具有与他莫昔芬相似的药理学特征。相比之下，新的纯抗雌激素有一个独特的作用机制，将是有价值的，无论是作为一线治疗晚期乳腺癌或作为二线内分泌治疗后，长期辅助他莫昔芬therapy.Finally失败，一个新的策略正在开发利用amtiestrogens的靶位点特异性作用。雷洛昔芬是一种对雌激素受体具有高亲和力但对子宫仅有弱雌激素活性的抗雌激素，可预防大鼠乳腺肿瘤发生并维持骨密度。该药物将作为骨质疏松症的治疗药物进行评估，但也可能在广泛的治疗受试者中预防乳腺癌和子宫内膜癌的发展。雌激素受体作为治疗机会的靶点的鉴定已被证明对控制乳腺癌非常有益，并具有控制女性骨质疏松症和冠心病的额外潜力。
In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (eds) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.e. greater than one year) has proven efficacy to enhance the survival of breast cancer patients. In addition, because there is an associated 40% decrease in contralateral breast cancer during adjuvant tamoxifen therapy and tamoxifen maintains bone density and reduces fatal myocardial infarction, clinical trials to test the worth of tamoxifen as a preventive for breast cancer in high risk women have started in the United States, United Kingdom, and Italy. Initial concerns that long-term tamoxifen causes endometrial cancer have been placed in perspective and analyzed by a review of the literature. Tamoxifen only doubles the normal risk of detecting endometrial cancer, (i.e. to 2 per 1,000 tamoxifen-treated women per year), and 80% of these cases are early stage, good prognosis disease. Annual gynecological examinations and education are essential to provide reassurance for patients.The success of tamoxifen has encouraged the development of new antiestrogens to exploit the estrogen receptor as a therapeutic target. Droloxifene and TAT-59 mimic the metabolite 4-hydroxytamoxifen in having a high affinity for the estrogen receptor (Jordan et al, J Endocrinol 75:305, 1977). These drugs appear to have a pharmacological profile similar to tamoxifen. In contrast, the new pure antiestrogens have a distinct mechanism of action and will be valuable either as a first line therapy for advanced breast cancer or as a second line endocrine therapy after the failure of long-term adjuvant tamoxifen therapy.Finally, a new strategy is being developed to exploit the target site specific action of amtiestrogens. Raloxifene, an antiestrogen with high affinity for the estrogen receptor but only weak estrogenicity for the uterus, prevents rat mammary tumorigenesis and maintains bone denstry. The drug is to be evaluated as a treatment for osteoporosis, but may also prevent the development of breast and endometrial cancer in a broad group of treated subjects.The identification of the estrogen receptor as a target for therapeutic opportunities has proved to be extremely beneficial for the control of breast cancer and has the added potential to control osteoporosis and coronary heart disease in women.