肿瘤细胞GS酶催化内源性谷氨酰胺合成在谷氨酰胺酵解（glutaminolysis）中的作用及其13N-NH3检测

以肿瘤谷氨酰胺酵解（Glutaminolysis）为靶标的分子影像和分子治疗研究是近期肿瘤研究的热点。本研究通过观察体外培养肿瘤细胞急、慢性谷氨酰胺剥夺、不同浓度氨以及谷氨酰胺合成酶（GS）抑制对肿瘤细胞内氨和谷氨酰胺浓度，氧化损伤、凋亡和自噬，GS酶表达及活性，以及其对细胞增殖的影响，研究证实肿瘤细胞GS酶催化内源性谷氨酰胺合成是Glutaminolysis代谢底物重要来源和代谢产物氨的主要代谢去路，当细胞外液谷氨酰胺耗竭时，肿瘤细胞通过GS酶表达上调使内源性谷氨酰胺合成代偿性增加；通过肿瘤细胞13N-NH3和13N-Glutamine摄取试验和荷瘤鼠系列microPET/CT显像，研究证实13N-NH3通过反映GS酶催化内源性谷氨酰胺合成检测肿瘤Glutaminolysis，随着肿瘤进行性生长，13N-NH3比13N-Glutamine检测肿瘤Gutaminolysis具有更高灵敏度。

Recently, many researchers concern on glutaminolysis pathways in tumor as targets for cancer imaging and therapy. Glutamine synthetase (GS; EC 6.3.1.2) is the only known human enzyme capable of catalyzing glutamine synthesis from ammonia and glutamate.We speculate glutamine synthesis from ammonia and glutamine catalyzed by GS in tumor cytosole play the role of providing glutamine for glutaminolysis, especially in the conditions of glutamine depletion in blood circulation and in tumors when tumors progressing,and detoxifing ammonia from glutaminolysis. A series of in vitro cell uptake and in vivo animal studies were performed to demonstrate tumor cell addiction to glutamine. Cell uptake studies of 13N-NH3 and 13N-Glutamine are performed in SF188 glioblastoma tumor cells, TSE human breast cancer cells and PC3 prostate cancer cells. A series of small-animal PET/CT studies of 13N-NH3 and 13N-Glutamine are conducted in the tumor-bearing rats with methylcholanthrene-induced fibrosarcoma cells to investigate the influense of progressive tumor growth on glutamine synthesis and glutamine uptake in tumors. The predicted results may support that 13N-NH3 is selectively taken up and trapped by tumor cells. It may be useful as a novel metabolic PET tracer for tumor imaging for the study of a fundamental change in tumor metabolism with high-rate glutaminolysis,and with higher sensitivity than 13N-Glutamine.