Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography–tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.
他莫昔芬作为一种选择性雌激素受体调节剂，常用于雌激素受体阳性乳腺癌的辅助药物治疗。尽管该药物能有效降低癌症复发率，但患者常报告出现认知和情感方面的不良副作用。然而，慢性他莫昔芬暴露对大脑的影响尚不明确，且现有啮齿动物模型未能复现患者长期口服给药的治疗模式。为此，我们采用长期自由摄食给药饲料的方式，建立临床相关性的慢性他莫昔芬暴露模型。成年雌性Long-Evans Hooded大鼠持续摄入含他莫昔芬的药用饲料约12周，对照组则接受标准饲料。实验结束后采集血液与脑组织样本进行分析。通过新型超高效液相色谱-串联质谱法检测血液他莫昔芬浓度，发现该给药模式产生的血清药物浓度与人类患者相当。采用免疫组织化学法观察海马区脑源性神经营养因子的表达情况，发现长期口服他莫昔芬可导致海马多个亚区BDNF表达下调。本研究不仅建立了慢性口服他莫昔芬暴露的新型建模与检测方法，同时为解释患者出现的认知行为改变提供了潜在机制。
肿瘤(癌症)患者之家