Biologic activity of tamoxifen at low doses in healthy women
Biologic activity of tamoxifen at low doses in healthy women
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DOI：
10.1093/jnci/90.19.1461
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发表时间：
1998-10-07
期刊：
影响因子：
--
通讯作者：
Veronesi, U
中科院分区：
文献类型：
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作者：
Decensi, A;Bonanni, BD;Veronesi, U
背景资料：最近在美国完成的一项临床试验结果表明，对高危女性给予他莫昔芬（20毫克/天）可以将乳腺癌发病率降低约50%，但与发生子宫内膜癌和静脉血栓栓塞事件的风险增加有关。由于这些不良反应可能与剂量有关，我们研究了当他莫昔芬的剂量低于目前使用的剂量时，它对几种生物标志物的影响。研究方法：在两个连续实验中，将127名年龄为35-70岁的健康直肠切除女性随机分配到以下四个治疗组之一：安慰剂（n = 31）或他莫昔芬20 mg/天（n = 30）（第一个实验）;或他莫昔芬10 mg/天（n = 34）或他莫昔芬10 mg/隔日（n = 32）（第二个实验）。比较以下参数的基线和2个月测量值：1）总胆固醇（主要终点）和心血管疾病的其他替代标志物，低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、甘油三酯和脂蛋白（a）; 2）血细胞计数; 3）纤维蛋白原; 4）抗凝血酶III; 5）骨钙素;以及，6）在103名女性的亚组中，胰岛素样生长因子-I（IGF-I），一种可能的乳腺癌替代标记物。结果：校正基线值后，所有三个他莫昔芬治疗组的总胆固醇和IGF-I循环水平均降低相同幅度。对于大多数其他参数，观察到类似的模式。在安慰剂组中，纤维蛋白原水平降低，是唯一表现出变化的参数。结论：他莫昔芬常规剂量降低高达75%（即，20 mg/天）不影响药物对大量生物标志物的活性，其中大多数是心血管疾病的替代标志物。这项研究是假设生成的，需要更大规模的研究来评估低剂量他莫昔芬的疗效。
Background: Results of a clinical trial recently completed in the United States indicate that administration of tamoxifen (20 mg/day) to women at risk can reduce breast cancer incidence by approximately 50% but is associated with an increased risk of developing endometrial cancer and venous thromboembolic events. Since these adverse effects may be dose related, we investigated the effect of tamoxifen on several biomarkers when the drug was given at doses lower than those currently in use. Methods: In two sequential experiments, 127 healthy hysterectomized women aged 35-70 years were randomly assigned to one of the following four treatment arms: placebo (n = 31) or tamoxifen at 20 mg/day (n = 30) (first experiment); or tamoxifen at 10 mg/day (n = 34) or tamoxifen at 10 mg/alternate days (n = 32) (second experiment). Baseline and 2-month measurements of the following parameters were compared: 1) total cholesterol (primary end point) and other surrogate markers of cardiovascular disease, e.g., low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a); 2) blood cell count; 3) fibrinogen; 4) antithrombin III; 5) osteocalcin; and, 6) in a subgroup of 103 women, insulin-like growth factor-I (IGF-I), a possible surrogate marker for breast cancer. Resuits: After adjustment for the baseline values, there were reductions in circulating levels of total cholesterol and IGF-I of the same magnitude in all three tamoxifen treatment arms. A similar pattern was observed for most of the other parameters. In the placebo arm, fibrinogen level, which showed a decrease, was the only parameter exhibiting change, Conclusions: Up to a 75% reduction in the conventional dose of tamoxifen (i.e., 20 mg/day) does not affect the activity of the drug on a large number of biomarkers, most of which are surrogate markers of cardiovascular disease. This study was hypothesis generating, and larger studies are warranted to assess the efficacy of tamoxifen at low doses.