Kagawa Shinya, Nishii Ryuichi, Higashi Tatsuya, Yamauchi Hiroshi, Ogawa Emi, Okudaira Hiroyuki, Kobayashi Masato, Yoshimoto Mitsuyoshi, Shikano Naoto, Kawai Keiichi
Division of PET Imaging, Shiga Medical Center Research Institute, Shiga, Japan; Division of Health Sciences, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.
Division of PET Imaging, Shiga Medical Center Research Institute, Shiga, Japan; Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, Chiba, Japan.
Nucl Med Biol. 2017 Jun;49:8-15. doi: 10.1016/j.nucmedbio.2017.01.008. Epub 2017 Jan 26.
To clarify the difference between system A and L amino acid transport imaging in PET clinical imaging, we focused on the use of α-[N-methyl-C]-methylaminoisobutyric acid ([C]MeAIB), and compared it with [S-methyl-C]-L-methionine ([C]MET). The aim of this study was to assess the correlation of accumulation of these two radioactive amino acid analogs with expression of amino acid transporters and cell proliferative activity in carcinoma cells.
Amino acid uptake inhibitor studies were performed in four human carcinoma cells (epidermal carcinoma A431, colorectal carcinoma LS180, and lung carcinomas PC14/GL and H441/GL) using the radioisotope analogs [H]MET and [C]MeAIB. MeAIB was used to inhibit the A system and 2-amino-2-norbornane-carboxylic acid (BCH) was used to inhibit the L system. The carcinoma gene expression levels of a number of amino acid transporters were measured by microarray and quantitative polymerase chain reaction. Carcinoma proliferative activity was assessed using accumulation of [methyl-H]-3'-deoxy-3'-fluorothymidine ([H]FLT).
[C]MeAIB uptake occurred principally via a Na-dependent A type mechanism whereas [H]MET uptake occurred predominantly via a Na-independent L type mechanism although other transporters were also utilized depending on cell type. There was no correlation between [H]MET uptake and total system L amino acid transporter (LAT) expression. In contrast, [C]MeAIB uptake strongly correlated with total system A amino acid transporter (SNAT) expression and proliferative activity in this preliminary study using four human carcinoma cell lines. Carcinoma proliferative activity also correlated with total SNAT expression. Advances in Knowledge and Implications for Patient Care: Because there is a significant correlation between the accumulation of [C]MeAIB and the gene expression level of total SNAT as well as the accumulation of [H]FLT, it is suggested that use of the analog [C]MeAIB in PET may provide an indication of tumor cell proliferative activity. [C]MeAIB is therefore expected to be very useful in PET imaging.
为了阐明正电子发射断层扫描（PET）临床成像中A系统和L型氨基酸转运成像之间的差异，我们重点研究了α-[N-甲基-C]-甲基氨基异丁酸（[C]MeAIB）的应用，并将其与[S-甲基-C]-L-蛋氨酸（[C]MET）进行比较。本研究的目的是评估这两种放射性氨基酸类似物的蓄积与癌细胞中氨基酸转运体表达及细胞增殖活性之间的相关性。
使用放射性同位素类似物[H]MET和[C]MeAIB，在四种人类癌细胞（表皮癌A431、结肠直肠癌LS180以及肺癌PC14/GL和H441/GL）中进行氨基酸摄取抑制剂研究。使用MeAIB抑制A系统，使用2-氨基-2-降冰片烷羧酸（BCH）抑制L系统。通过微阵列和定量聚合酶链反应测量多种氨基酸转运体的癌基因表达水平。使用[甲基-H]-3'-脱氧-3'-氟胸苷（[H]FLT）的蓄积评估癌增殖活性。
[C]MeAIB摄取主要通过钠依赖性A型机制发生，而[H]MET摄取主要通过非钠依赖性L型机制发生，不过其他转运体也会根据细胞类型被利用。[H]MET摄取与总L系统氨基酸转运体（LAT）表达之间无相关性。相比之下，在这项使用四种人类癌细胞系的初步研究中，[C]MeAIB摄取与总A系统氨基酸转运体（SNAT）表达及增殖活性密切相关。癌增殖活性也与总SNAT表达相关。知识进展及对患者护理的意义：由于[C]MeAIB的蓄积与总SNAT的基因表达水平以及[H]FLT的蓄积之间存在显著相关性，因此建议在PET中使用类似物[C]MeAIB可能提供肿瘤细胞增殖活性的指标。因此，[C]MeAIB有望在PET成像中非常有用。
