Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy. Laboratory investigation.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Miyazaki
Takeshi
T
Department of Neurosurgery, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan. takeshi@med.shimane-u.ac.jp
Moritake
Kouzo
K
Yamada
Kazuo
K
Hara
Nobumasa
N
Osago
Harumi
H
Shibata
Tomoko
T
Akiyama
Yasuhiko
Y
Tsuchiya
Mikako
M
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000032:analysis / Q000037:antagonists & inhibitors*; D007371:Interferon-gamma / Q000494:pharmacology; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C028129:tryptophan methyl ester; D007371:Interferon-gamma; D014364:Tryptophan