Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
J Transl Med. 2015 Apr 9;13:114. doi: 10.1186/s12967-015-0458-4.
Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.
High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm.
The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.
Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.
多西紫杉醇是治疗乳腺癌最常用的药物之一。然而，对多西紫杉醇的耐药或反应不完全是一个主要挑战。本研究旨在利用磁共振代谢组学技术，在 BRCA1 突变型乳腺癌的小鼠模型中，鉴定多西紫杉醇耐药的潜在生物标志物。
对来自对多西紫杉醇敏感或耐药的 BRCA1 突变型乳腺肿瘤的小鼠组织样本进行高分辨魔角旋转（HRMAS）（1）H 磁共振波谱分析。在给予 25mg/kg 多西紫杉醇剂量之前、1-2 天、3-5 天和 6-7 天进行测量。通过多元分析对 MR 光谱进行分析，然后通过峰拟合分析个别化合物的信号，并与肌酸信号的积分和 2.9-3.6ppm 之间的所有信号的积分进行归一化。
HRMAS 光谱显示敏感和耐药组织样本之间存在显著的代谢差异。特别是，与肌酸相比，耐药肿瘤中的胆碱代谢物增加了 50%以上，与 2.9-3.6ppm 之间的所有信号相比增加了 30%以上。在治疗后不久（1-2 天），敏感组的归一化胆碱代谢物水平显著增加了 30%以上，与多西紫杉醇诱导的最高细胞凋亡活性时间一致。此后，这些肿瘤中的胆碱代谢物恢复到治疗前的水平。在整个研究过程中，耐药肿瘤中的胆碱化合物没有变化。
在多西紫杉醇耐药的 BRCA1 突变型小鼠乳腺肿瘤中，胆碱化合物的组织浓度比在敏感肿瘤中更高，但仅在敏感肿瘤中，在多西紫杉醇治疗后的最初几天观察到这些化合物的增加。因此，胆碱化合物的治疗前和治疗后组织水平都有可能预测对多西紫杉醇治疗的反应。
