Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage
Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage
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DOI：
10.1007/s00259-008-0888-9
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发表时间：
2008-12-01
影响因子：
9.1
通讯作者：
Overgaard, Jens
中科院分区：
文献类型：
--
作者：
Busk, Morten;Horsman, Michael R.;Overgaard, Jens
目的 肿瘤缺氧和糖酵解升高（Warburg 效应）预示预后不良。每个参数都可以通过正电子发射断层扫描单独评估，但它们通过无氧糖酵解（巴斯德效应）联系起来。在这里，我们比较了氟阿糖苷 ([(18)F]FAZA)（一种有前途但尚未充分表征的缺氧特异性示踪剂）和氟脱氧葡萄糖 ([(18)F]FDG) 在四种癌细胞系中的氧合依赖性保留。方法将接种在盖玻片上的细胞放置在改良的培养皿中，使物理分离的细胞能够共享相同的含有示踪剂的培养基池。在有氧、缺氧或缺氧示踪剂孵育后，分析盖玻片的放射性（[(18)F]FDG+[(18)F]FAZA）或在无示踪剂的含氧培养基中重新孵育，然后测量（[(18)F]FAZA）。接下来，我们测试了 [(18)F]FDG 作为葡萄糖代谢率相对测量值的可靠性。最后，在小鼠体内建立了两种细胞系的异种移植物，并从组织切片中推断出缺氧区域和氧合良好区域之间的示踪剂分布。结果 三小时缺氧强烈刺激 [(18)F]FAZA 保留，缺氧与有氧摄取比率通常高于 30。 四分之三的细胞系表现出与葡萄糖相似的 [(18)F]FDG 选择性，但有氧摄取和[(18)F]FDG 的缺氧与有氧摄取比率变化很大。尽管不太明显，但与 [(18)F]FDG 相比，[(18)F]FAZA 也表现出优异的体内缺氧特异性。结论 [(18)F]FAZA 在缺氧成像方面表现出优异的体外特征，包括适度的细胞间变异性和在含氧细胞中不结合。相比之下，由于基线（有氧）葡萄糖代谢和巴斯德效应的幅度存在较大差异，[(18)F]FDG 作为缺氧替代标志物的可用性值得怀疑。
Purpose Tumour hypoxia and elevated glycolysis (Warburg effect) predict poor prognosis. Each parameter is assessable separately with positron emission tomography, but they are linked through anaerobic glycolysis (Pasteur effect). Here, we compare the oxygenation-dependent retention of fluoroazomycin arabinoside ([(18)F]FAZA), a promising but not well-characterised hypoxia-specific tracer, and fluorodeoxyglucose ([(18)F]FDG) in four carcinoma cell lines.Methods Cells seeded on coverslips were positioned in modified Petri dishes that allow physically separated cells to share the same tracer-containing medium pool. Following oxic, hypoxic or anoxic tracer incubation, coverslips were analysed for radioactivity ([(18)F]FDG+[(18)F]FAZA) or re-incubated in tracer-free oxygenated medium and then measured ([(18)F]FAZA). Next, we tested the reliability of [(18)F]FDG as a relative measure of glucose metabolic rate. Finally, from two cell lines, xenografts were established in mice, and the tracer distribution between hypoxic and well-oxygenated areas were deduced from tissue sections.Results Three hours of anoxia strongly stimulated [(18)F]FAZA retention with anoxic-to-oxic uptake ratios typically above 30. Three out of four cell lines displayed similar selectivity of [(18)F]FDG versus glucose, but oxic uptake and anoxic-to-oxic uptake ratio of [(18)F]FDG varied considerably. Although less pronounced, [(18)F]FAZA also showed superior in vivo hypoxia specificity compared with [(18)F]FDG.Conclusions [(18)F]FAZA displays excellent in vitro characteristics for hypoxia imaging including modest cell-to-cell line variability and no binding in oxic cells. In contrast, the usability of [(18)F]FDG as a surrogate marker for hypoxia is questionable due to large variations in baseline (oxic) glucose metabolism and magnitudes of the Pasteur effects.