Dhingra K
Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA.
Cancer Invest. 2001;19(6):649-59. doi: 10.1081/cnv-100104293.
Female hormones, especially estrogens, play an important role in the pathogenesis of breast neoplasms and are a principal determinant of their biological behavior. Endocrine manipulation through medical or surgical means can often lead to objective shrinkage of breast tumors. Tamoxifen, a triphenylethylene estrogen receptor modulator, is currently the most widely used hormonal treatment for breast cancer. It has been conclusively demonstrated to reduce the risk of relapse following definitive local therapy (and systemic chemotherapy, when indicated) of invasive or noninvasive breast cancer. Recently, it has also been shown to reduce the incidence of breast cancer in healthy women who are at high risk of developing the disease. In addition, it can prevent osteoporosis and reduce the risk of fractures in postmenopausal women. However, its use is also complicated by an increased incidence of endometrial hyperplasia/carcinoma, venous thromboembolism, cataracts, and in some cases, emergence of tamoxifen-dependent clones of breast cancer. These side effects (except cataracts) are believed to be related to estrogen-agonist effects of tamoxifen. Newer drugs, which are "pure antiestrogens" or inhibitors of estrogen biosynthesis, are devoid of such estrogen-agonist activity and may not have the liability of many of these side effects. However, these agents would also be expected to lack the potentially beneficial effects of tamoxifen on lipids and skeletal system. The ability of tamoxifen to act as an estrogen-agonist or estrogen-antagonist in a tissue-specific fashion has led to the concept of selective estrogen-receptor modulation. Selective estrogen receptor modulators (SERMs), which are devoid of estrogen-agonist effects on the uterus or breast cancer cells but retain potentially beneficial effects on bones and lipids, have been described as "ideal" SERMs. A number of such compounds are currently being tested. Raloxifene is already approved for prevention of osteoporosis and has potential efficacy for prevention and treatment of breast cancer. An analogue of raloxifene, LY353381, is currently in Phase II clinical trials for treatment of breast cancer, with promising early results. EM800 and CP336156 are other promising ideal SERMs in clinical trials. These compounds may provide better treatment and chemoprevention alternatives for breast cancer as compared to tamoxifen, aromatase inhibitors, and pure antiestrogens. In addition, they may also prove to be useful for the treatment and prevention of prostate cancer as well as for treating benign gynecological diseases such as fibroids and endometriosis. Future laboratory efforts should focus on further broadening the efficacy profile of SERMs (e.g., prevention of Alzheimer's disease and elevation of high-density lipoproteins to improve the likelihood of cardiovascular benefit) and narrowing their side-effect profile (e.g., risk of thromboembolism and hot flashes).
女性激素，尤其是雌激素，在乳腺肿瘤的发病机制中起着重要作用，并且是其生物学行为的主要决定因素。通过药物或手术手段进行内分泌调控常常可导致乳腺肿瘤出现客观缩小。他莫昔芬，一种三苯乙烯类雌激素受体调节剂，是目前乳腺癌最广泛使用的激素治疗药物。已经确凿证明它可降低浸润性或非浸润性乳腺癌进行确定性局部治疗（以及必要时进行全身化疗）后复发的风险。最近，还显示它可降低患乳腺癌风险高的健康女性中乳腺癌的发病率。此外，它可预防绝经后女性的骨质疏松并降低骨折风险。然而，其使用也因子宫内膜增生/癌、静脉血栓栓塞、白内障发病率增加而变得复杂，并且在某些情况下，会出现他莫昔芬依赖的乳腺癌克隆。这些副作用（白内障除外）被认为与他莫昔芬的雌激素激动剂作用有关。更新的药物，即“纯抗雌激素”或雌激素生物合成抑制剂，没有这种雌激素激动剂活性，可能也没有许多这些副作用。然而，预计这些药物也会缺乏他莫昔芬对脂质和骨骼系统的潜在有益作用。他莫昔芬能够以组织特异性方式充当雌激素激动剂或雌激素拮抗剂，这导致了选择性雌激素受体调节的概念。选择性雌激素受体调节剂（SERM），对子宫或乳腺癌细胞没有雌激素激动剂作用，但对骨骼和脂质保留潜在有益作用，已被描述为“理想”的SERM。目前正在测试许多这类化合物。雷洛昔芬已被批准用于预防骨质疏松，并且对乳腺癌的预防和治疗具有潜在疗效。雷洛昔芬的一种类似物LY353381目前正处于治疗乳腺癌的II期临床试验阶段，早期结果很有前景。EM800和CP336156是临床试验中其他有前景的理想SERM。与他莫昔芬、芳香化酶抑制剂和纯抗雌激素相比，这些化合物可能为乳腺癌提供更好的治疗和化学预防选择。此外，它们可能还被证明对前列腺癌的治疗和预防以及治疗诸如子宫肌瘤和子宫内膜异位症等良性妇科疾病有用。未来的实验室研究应集中于进一步拓宽SERM的疗效范围（例如，预防阿尔茨海默病以及提高高密度脂蛋白以增加心血管获益的可能性）并缩小其副作用范围（例如，血栓栓塞和潮热的风险）。
