Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways
Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways
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DOI：
10.1158/0008-5472.can-06-2346
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Demidem, Aicha
中科院分区：
文献类型：
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作者：
Morvan, Daniel;Demidem, Aicha
肿瘤代谢组学可以发现肿瘤生物标志物和代谢治疗靶点。应用二维质子高分辨魔角自旋核磁共振波谱代谢组学方法，研究了33例小鼠B16黑色素瘤和31例小鼠3LL肺癌经氯乙基亚硝基脲治疗后体内代谢物的变化。两种类型的治疗肿瘤在延迟后恢复生长。亚硝基脲引起DNA损伤，但遗传毒性应激的代谢后果知之甚少。虽然未治疗的肿瘤类型的代谢产物谱中观察到一些差异，但对亚硝基脲的反应的突出代谢特征是共同的。在生长抑制期，葡萄糖（超过X 10; P < 0.05）、谷氨酰胺（x 3 - 4; P < 0.01）和天冬氨酸（x 2 - 5; P < 0.01）蓄积。这种反应证明了核苷从头合成下调和药物疗效。然而，这一阶段也涉及丙氨酸的增加（在B16黑色素瘤中P < 0.001），琥珀酸的减少（P < 0.001）和丝氨酸衍生的代谢物（甘氨酸，磷酸乙醇胺和甲酸，P < 0.01）的积累。这种反应见证了参与能量产生的途径的激活和核苷酸从头合成的恢复，因此是DNA修复和适应治疗的代谢途径。在生长恢复期，与谷氨酰胺相比，它保持了多不饱和脂肪酸的积累（x1.5至2; P < 0.05），并减少了葡萄糖的利用（P < 0.05），这是适应的代谢指纹。因此，这项研究提供了原则的证据，即肿瘤对抗癌药物的反应的代谢组学可能有助于发现药物疗效和适应治疗的代谢途径。
Metabolomics of tumors may allow discovery of tumor biomarkers and metabolic therapeutic targets. Metabolomics by two-dimensional proton high-resolution magic angle spinning nuclear magnetic resonance spectroscopy was applied to investigate metabolite disorders following treatment by chloroethylnitrosourea of murine B16 melanoma (n = 33) and 3LL pulmonary carcinoma (n = 31) in vivo. Treated tumors of both types resumed growth after a delay. Nitrosoureas provoke DNA damage but the metabolic consequences of genotoxic stress are little known yet. Although some differences were observed in the metabolite profile of untreated tumor types, the prominent metabolic features of the response to nitrosourea were common to both. During the growth inhibition phase, there was an accumulation of glucose (more than X 10; P < 0.05), glutamine (x3 to 4; P < 0.01), and aspartate (x2 to 5; P < 0.01). This response testified to nucleoside de novo synthesis down-regulation and drug efficacy. However, this phase also involved the increase in alanine (P < 0.001 in B16 melanoma), the decrease in succinate (P < 0.001), and the accumulation of serine-derived metabolites (glycine, phosphoethanolamine, and formate, P < 0.01). This response witnessed the activation of pathways implicated in energy production and resumption of nucleotide de novo synthesis, thus metabolic pathways of DNA repair and adaptation to treatment. During the growth recovery phase, it remained polyunsaturated fatty acid accumulation (x1.5 to 2; P < 0.05) and reduced utilization of glucose compared with glutamine (P < 0.05), a metabolic fingerprint of adaptation. Thus, this study provides the proof of principle that metabolomics of tumor response to an anticancer agent may help discover metabolic pathways of drug efficacy and adaptation to treatment.