Wu F, Bergström M, Stridsberg M, Orlefors H, Eriksson B, Oberg K, Watanabe Y, Långstrom B
Uppsala University PET Centre, Sweden.
Anticancer Res. 1997 Jul-Aug;17(4A):2363-7.
The induction of glutamine starvation has been suggested as a potential target for antitumoral treatment using inhibitors of amidotransferase, an enzyme which mediates the conversion of glutamate to glutamine. Using multicellular aggregates from tumor cell lines, the effect of treatment with a suggested glutamine antagonist, 6-diazo-5-axo-L-norleucine (DON), was investigated. As indicators of treatment response, three different parameters were measured: aggregate size, uptake of 14C-methionine and secretion of Chromogranin A. Of six cell types evaluated (carcinoid, glioma, neuroblastoma pancreas and bladder cancer), the largest inhibition of 14Cmethionine uptake, amounting to 60%, was found in the carcinoid cell line BON. In this cell line the maximum effect was reached already at 10 microM concentration. DON induced marked growth inhibition in the BON aggregates which lasted 3-4 weeks after which regrowth started. During this period the secretion of chromogranin and methionine uptake was also inhibited. These studies suggest that the neuroendocrine cell line BON is especially vulnerable to treatment by DON and show that strong inhibitory effects are found at concentrations lower than that achieved in patient blood in previous clinical trials.
谷氨酰胺饥饿诱导已被提议作为使用酰胺转移酶抑制剂进行抗肿瘤治疗的潜在靶点，酰胺转移酶是一种介导谷氨酸转化为谷氨酰胺的酶。利用肿瘤细胞系的多细胞聚集体，研究了一种建议的谷氨酰胺拮抗剂6-重氮-5-氧代-L-正亮氨酸（DON）的治疗效果。作为治疗反应的指标，测量了三个不同参数：聚集体大小、14C-甲硫氨酸摄取量和嗜铬粒蛋白A分泌量。在评估的六种细胞类型（类癌、胶质瘤、神经母细胞瘤、胰腺和膀胱癌）中，在类癌细胞系BON中发现对14C-甲硫氨酸摄取的最大抑制，达到60%。在该细胞系中，在10 microM浓度时已达到最大效应。DON在BON聚集体中诱导明显的生长抑制，持续3-4周，之后开始重新生长。在此期间，嗜铬粒蛋白的分泌和甲硫氨酸摄取也受到抑制。这些研究表明神经内分泌细胞系BON对DON治疗特别敏感，并表明在低于先前临床试验中患者血液中所达到的浓度时就发现了强烈的抑制作用。
