The anti-oestrogen tamoxifen, which is widely used as adjuvant therapy for breast cancer, is undergoing evaluation as a chemopreventive agent in women at increased risk of developing this disease. Recent results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 prevention trial show a 49% reduction in breast cancer incidence in healthy, high-risk women. However, tamoxifen treatment has the serious side effect of increasing the incidence of endometrial cancer in women and long-term administration of tamoxifen causes hepatic tumours in rats. These liver tumours are induced via a genotoxic mechanism, but the mechanisms responsible for endometrial cancer in women are not yet known and are a focus of much debate. This review describes the findings from the chemoprevention trials and problems associated with the use of tamoxifen in this setting. The mechanism of carcinogenesis in rat liver is explained in detail and compared to the situation in humans, with a view to assessing the risks associated with tamoxifen therapy and predicting whether other anti-oestrogens might be safer alternatives.

译文

抗雌激素他莫昔芬被广泛用作乳腺癌的辅助治疗,目前正在接受评估,作为一种化学预防剂,在罹患这种疾病的风险增加的女性中。国家外科辅助乳房和肠项目 (NSABP) P-1预防试验的最新结果表明,健康,高危女性的乳腺癌发病率降低了49%。然而,他莫昔芬治疗具有增加女性子宫内膜癌发生率的严重副作用,并且长期服用他莫昔芬会导致大鼠肝肿瘤。这些肝脏肿瘤是通过遗传毒性机制诱导的,但是女性子宫内膜癌的机制尚不清楚,并且是许多争论的焦点。这篇综述描述了化学预防试验的发现以及在这种情况下使用他莫昔芬的相关问题。详细解释了大鼠肝脏的致癌机制,并将其与人类的情况进行了比较,以评估与他莫昔芬治疗相关的风险并预测其他抗雌激素药物是否可能是更安全的替代品。

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