Jordan V C
Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611.
Breast Cancer Res Treat. 1994;31(1):41-52. doi: 10.1007/BF00689675.
The success of antiestrogen therapy to treat all stages of breast cancer, and the evaluation of tamoxifen as a preventive for breast cancer in normal women, have focused attention on the molecular mechanisms of antiestrogen action and mechanisms of drug resistance. The overall goal of research is to enhance current therapies and to develop new approaches for breast cancer treatment and prevention. Recent studies show that tamoxifen and the new pure antiestrogens appear to have different mechanisms of action: tamoxifen and related compounds cause a change in the folding of the steroid binding domain that prevents gene activation whereas the pure antiestrogens cause a reduced interaction at response elements and cause a rapid loss of receptor complexes. Tamoxifen treatment produces changes in the cellular and circulating levels of growth factors that could influence both receptor negative or receptor positive tumor growth and the metastatic potential of a tumor. These events may explain the survival advantage observed with tamoxifen therapy. However, the current therapeutic challenge is to avoid drug resistance during long-term tamoxifen therapy. Numerous explanations for drug resistance to tamoxifen have been suggested, including elevated estrogen levels, increased tumor antiestrogen binding sites, receptor mutations, and impaired signal transduction. However, it is probable that multiple mechanisms evolve to facilitate tumor survival. Most importantly, current research is examining mechanisms responsible for the beneficial actions of tamoxifen on bones and lipids as well as the potentially deleterious effects of tamoxifen on liver and endometrial carcinogenesis and retinopathy. The urgent need to understand antiestrogenic drug mechanisms and toxicity is being facilitated by the application of the technology developed for basic molecular biology.
抗雌激素疗法在治疗乳腺癌各阶段的成功，以及他莫昔芬作为正常女性乳腺癌预防药物的评估，已将注意力集中在抗雌激素作用的分子机制和耐药机制上。研究的总体目标是加强当前的治疗方法，并开发乳腺癌治疗和预防的新方法。最近的研究表明，他莫昔芬和新型纯抗雌激素似乎具有不同的作用机制：他莫昔芬及相关化合物会导致类固醇结合域的折叠发生变化，从而阻止基因激活，而纯抗雌激素会导致在反应元件处的相互作用减少，并导致受体复合物迅速丢失。他莫昔芬治疗会使生长因子的细胞水平和循环水平发生变化，这可能会影响受体阴性或受体阳性肿瘤的生长以及肿瘤的转移潜能。这些事件可能解释了他莫昔芬治疗所观察到的生存优势。然而，当前的治疗挑战是在长期他莫昔芬治疗期间避免耐药性。针对他莫昔芬耐药性提出了许多解释，包括雌激素水平升高、肿瘤抗雌激素结合位点增加、受体突变和信号转导受损。然而，可能会出现多种机制来促进肿瘤存活。最重要的是，当前的研究正在研究他莫昔芬对骨骼和脂质的有益作用以及他莫昔芬对肝脏、子宫内膜癌发生和视网膜病变的潜在有害作用的机制。为基础分子生物学开发的技术的应用促进了对抗雌激素药物机制和毒性的迫切理解需求。
