Miyazaki Takeshi, Moritake Kouzo, Yamada Kazuo, Hara Nobumasa, Osago Harumi, Shibata Tomoko, Akiyama Yasuhiko, Tsuchiya Mikako
Department of Neurosurgery, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan.
J Neurosurg. 2009 Aug;111(2):230-7. doi: 10.3171/2008.10.JNS081141.
Indoleamine 2,3-dioxygenase (IDO), a kynurenine pathway (KP) enzyme catalyzing oxidation of the essential amino acid tryptophan (Trp), is thought to be involved in the immune resistance of malignant tumors through T-cell inactivation caused by Trp depletion and metabolite accumulation. Human malignant gliomas may use this strategy to escape immune attack. The object of this study was to investigate the possibility of IDO-dependent Trp depletion by malignant gliomas and the practicability of using an IDO inhibitor together with anticancer drugs to reserve Trp without decreasing the cytotoxicity of the drugs.
The authors studied expression of IDO and other KP enzymes and the effects of an IDO inhibitor, 1-methyl L-tryptophan (1MT), on Trp metabolism and cytotoxicity of anticancer drugs, together with direct measurement of KP metabolites, in cultured human malignant glioma cells.
Upon interferon-gamma (IFN-gamma) stimulation, the glioma cells greatly increased their IDO mRNA expression concomitant with depletion of Trp. The IDO inhibitor 1MT successfully prevented Trp consumption by the stimulated glioma cells. Combining 1MT with anticancer drugs (temozolomide, bischloroethylnitrosourea [BCNU], etoposide and cisplatin) did not interfere with the drugs' suppression of growth of LN229 glioma cells but rather increased their inhibitory effects on IDO activity.
These findings suggest that the robust IDO expression with rapid consumption of Trp in human glioma cells induced by IFN-gamma could lead to immune resistance in glioma cells. Indoleamine 2,3-dioxygenase inhibitors that prevent Trp depletion could be used with anticancer drugs to improve therapeutic effects.
吲哚胺2,3-双加氧酶（IDO）是犬尿氨酸途径（KP）中的一种酶，可催化必需氨基酸色氨酸（Trp）的氧化，被认为通过色氨酸耗竭和代谢产物积累导致的T细胞失活参与恶性肿瘤的免疫抵抗。人类恶性胶质瘤可能利用这种策略逃避免疫攻击。本研究的目的是探讨恶性胶质瘤依赖IDO导致色氨酸耗竭的可能性，以及使用IDO抑制剂与抗癌药物联合使用以保留色氨酸而不降低药物细胞毒性的可行性。
作者研究了IDO和其他KP酶的表达，以及IDO抑制剂1-甲基-L-色氨酸（1MT）对培养的人类恶性胶质瘤细胞中色氨酸代谢和抗癌药物细胞毒性的影响，并直接测量了KP代谢产物。
在干扰素-γ（IFN-γ）刺激下，胶质瘤细胞的IDO mRNA表达大幅增加，同时色氨酸耗竭。IDO抑制剂1MT成功地阻止了受刺激的胶质瘤细胞消耗色氨酸。将1MT与抗癌药物（替莫唑胺、双氯乙基亚硝脲[BCNU]、依托泊苷和顺铂）联合使用不会干扰药物对LN229胶质瘤细胞生长的抑制作用，反而增强了它们对IDO活性的抑制作用。
这些发现表明，IFN-γ诱导的人类胶质瘤细胞中IDO的强烈表达和色氨酸的快速消耗可能导致胶质瘤细胞的免疫抵抗。防止色氨酸耗竭的吲哚胺2,3-双加氧酶抑制剂可与抗癌药物联合使用以提高治疗效果。
