Department of Neurosurgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
Nucl Med Biol. 2013 Aug;40(6):808-15. doi: 10.1016/j.nucmedbio.2013.04.007. Epub 2013 May 21.
Amino acid PET tracers are promising for visualizing gliomas and evaluating radiochemotherapeutic effects. We compared the glioma detection and early response assessment utility between trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) by simultaneously analyzing their uptake by rat gliomas treated with and without temozolomide (TMZ) in vitro and in vivo.
C6 rat gliomas were incubated with low-dose TMZ to induce chemoresistance. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated a significantly greater surviving fraction in the TMZ-resistant subline (C6R) than in drug-naive cells (C6). The anti-(14)C-FACBC and (3)H-Met uptakes were quantified using a triple-label accumulation assay to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation rate) in tumor cells. C6 and C6R cells were inoculated into the right and left basal ganglia, respectively, of rats. Efficacy of TMZ against the orthotopic gliomas was analyzed by MRI, Evans blue extravasation, anti-(14)C-FACBC and (3)H-Met autoradiography, and MIB-5 proliferation index.
The (3)H-TdR accumulation rate and amino acid tracer (anti-(14)C-FACBC and (3)H-Met) uptake significantly decreased 48 and 72 h, respectively, after TMZ treatment in C6 but not C6R cells. Anti-(14)C-FACBC uptake correlated significantly with (3)H-Met uptake and the (3)H-TdR accumulation rate. In the intracerebral glioma model, anti-(14)C-FACBC and (3)H-Met autoradiography clearly delineated the tumor extent, which spread well beyond the high-T2-intensity and enhancing lesions visible on MRI and Evans blue extravasation. TMZ significantly decreased anti-(14)C-FACBC and (3)H-Met uptake and the MIB-5 index of C6 but not C6R tumors. TMZ inhibited tracer uptake and tumor proliferation before morphological changes on MRI.
Anti-(14)C-FACBC, like (3)H-Met, was more sensitive than post-contrast T1-weighted MRI for detecting tumor extent and early tumor response to TMZ treatment. Anti-(18)F-FACBC should be a sensitive and precise imaging biomarker for tumor extent visualization and response assessment in glioma patients.
氨基酸 PET 示踪剂在显示神经胶质瘤和评估放化疗效果方面具有广阔的应用前景。我们通过对比体外和体内实验中接受和未接受替莫唑胺（TMZ）治疗的大鼠神经胶质瘤对反式-1-氨基-3-氟-1-(14)C-环丁烷羧酸（anti-(14)C-FACBC）和 (3)H-甲基-L-蛋氨酸 ((3)H-Met) 的摄取情况，来比较这两种示踪剂在神经胶质瘤检测和早期疗效评估方面的作用。
采用低剂量 TMZ 处理 C6 大鼠神经胶质瘤细胞，诱导其产生化疗耐药性。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）实验结果显示，与未经药物处理的细胞（C6）相比，TMZ 耐药亚系（C6R）的存活分数明显更高。通过三标记累积实验来定量分析 anti-(14)C-FACBC 和 (3)H-Met 的摄取情况，以研究示踪剂摄取与肿瘤细胞增殖（(3)H-胸苷（TdR）累积率）之间的关系。将 C6 和 C6R 细胞分别接种到大鼠右侧和左侧基底神经节。采用 MRI、伊文思蓝外渗、anti-(14)C-FACBC 和 (3)H-Met 放射自显影以及 MIB-5 增殖指数分析 TMZ 对原位神经胶质瘤的疗效。
在 C6 细胞中，TMZ 处理 48 和 72 小时后，(3)H-TdR 累积率和氨基酸示踪剂（anti-(14)C-FACBC 和 (3)H-Met）摄取均显著降低，但 C6R 细胞中未见该变化。anti-(14)C-FACBC 摄取与 (3)H-Met 摄取和 (3)H-TdR 累积率显著相关。在颅内神经胶质瘤模型中，anti-(14)C-FACBC 和 (3)H-Met 放射自显影可清晰显示肿瘤范围，其范围明显超出 MRI 可见的高 T2 强度和增强病变以及伊文思蓝外渗范围。TMZ 可显著降低 C6 但不降低 C6R 肿瘤的 anti-(14)C-FACBC 和 (3)H-Met 摄取及 MIB-5 指数。TMZ 可在 MRI 出现形态学改变之前抑制示踪剂摄取和肿瘤增殖。
anti-(14)C-FACBC 与 (3)H-Met 一样，比增强后 T1 加权 MRI 更能敏感地检测肿瘤范围和对 TMZ 治疗的早期肿瘤反应。anti-(18)F-FACBC 有望成为神经胶质瘤患者肿瘤范围可视化和疗效评估的敏感、精确的影像学生物标志物。
