Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas.
Preclinical pharmacological evaluation of letrozole as a novel treatment for gliomas.
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letrozole作为神经胶质瘤的新型治疗方法的临床前药理评估。
DOI：
10.1158/1535-7163.mct-14-0743
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发表时间：
2015-04
影响因子：
5.7
通讯作者：
Desai PB
中科院分区：
文献类型：
--
作者：
Dave N;Chow LM;Gudelsky GA;LaSance K;Qi X;Desai PB
来曲唑是一种广泛用于治疗绝经后女性雌激素受体阳性乳腺肿瘤的芳香化酶抑制剂，我们目前的数据表明，来曲唑可能用于治疗胶质母细胞瘤。首先，我们测量了来曲唑和芳香化酶（CYP 19 A1）在人LN 229、T98 G、U373 MG、U251 MG和U87 MG以及大鼠C6胶质瘤细胞系中的表达和活性的体外细胞毒性。雌激素受体（ER）阳性MCF-7和ER阴性MDA-MB-231细胞作为对照。采用MTT法测定细胞毒性，并使用测定睾酮向雌激素转化的免疫测定法测定芳香酶活性。其次，在原位植入C6神经胶质瘤的Sprague-Dawley大鼠中评估来曲唑的体内活性。采用μPET/CT成像，使用[18 F]-氟脱氧葡萄糖（F18-FDG）作为放射性示踪剂，评估来曲唑治疗（4 mg/kg/天）的肿瘤体积变化。采集脑组织进行组织学评价。所有胶质瘤细胞系均表达CYP 19 A1，来曲唑对这些细胞具有相当大的细胞毒性，并降低芳香化酶活性（IC 50，0.1-3.5 μmol/L）。使用F18-FDG μPET/CT的成像分析显示，来曲唑治疗8天后，活动性肿瘤体积显著减小（>75%）。免疫组织化学分析显示，来曲唑治疗后，芳香化酶在脑肿瘤区域的表达显着减少。因此，采用多方面的工具，我们证明，芳香化酶可能是一个新的目标，用于治疗神经胶质瘤和来曲唑，FDA批准的药物，具有出色的安全记录，可用于治疗这种原发性脑肿瘤，目前有几个治疗选择。
We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor-positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague-Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing μPET/CT imaging, employing [18F]-fluorodeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines included here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1–3.5 μmol/L). Imaging analysis employing F18-FDG μPET/CT demonstrated a marked reduction of active tumor volume (>75%) after 8 days of letrozole treatment. Immunohistochemical analysis revealed marked reduction in aromatase expression in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aromatase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options.