Taneja Samir S, Smith Matthew R, Dalton James T, Raghow Sharan, Barnette Gary, Steiner Mitchell, Veverka Karen A
New York University School of Medicine, New York, NY 10016, USA.
Expert Opin Investig Drugs. 2006 Mar;15(3):293-305. doi: 10.1517/13543784.15.3.293.
Deregulation of the estrogen axis in humans prompts a series of tissue-specific events. In the breast and prostate, alterations in estrogen signalling lead to genotypic and phenotypic molecular alterations that result in dysplastic cellular appearance, deregulated cell growth and carcinoma. In bone, decreased estrogen leads to increased osteoclastogenesis and bone resorption, decreased bone mineral density and a significant fracture risk. Toremifene is a selective estrogen receptor modulator that exerts pharmacological activity in the breast, bone and prostate. An intense interest in developing this agent for prostate cancer chemoprevention is based on the reduction of premalignant and malignant prostate lesions in a transgenic model of prostate cancer. Biological and clinical activity was demonstrated in Phase II trials by the prevention of progression to prostate cancer in men with high-grade prostate intraepithelial neoplasia and through suppression of bone turnover biomarkers and increased bone mineral density in men on androgen deprivation therapy for prostate cancer.
人体雌激素轴失调会引发一系列组织特异性事件。在乳腺和前列腺中，雌激素信号的改变会导致基因型和表型分子改变，进而导致细胞发育异常、细胞生长失调和癌变。在骨骼中，雌激素减少会导致破骨细胞生成增加和骨吸收增加，骨矿物质密度降低以及骨折风险显著增加。托瑞米芬是一种选择性雌激素受体调节剂，在乳腺、骨骼和前列腺中发挥药理活性。对开发这种药物用于前列腺癌化学预防的浓厚兴趣基于在前列腺癌转基因模型中癌前和恶性前列腺病变的减少。在II期试验中，通过预防高级别前列腺上皮内瘤变男性进展为前列腺癌，以及通过抑制前列腺癌雄激素剥夺治疗男性的骨转换生物标志物和增加骨矿物质密度，证明了其生物学和临床活性。
