title: Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice.
abstract: Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-D-tryptophan (D-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of D-1MT, mice were killed on day 28. Serum concentrations of L-kynurenine and L-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-γ, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. D-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum L-kynurenine/L-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-γ and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and D-1MT+CY groups. The number of Tregs in TDLNs in the D-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that D-1MT in combination with CY is an effective treatment for lymphoma in a mouse model.
authors.affiliation: First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nakamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hara
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Ryoko
authors.initials: R
authors.lastname: Mabuchi
authors.forename: Junji
authors.initials: J
authors.lastname: Nagano
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kochi
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.forename: Naoe
authors.initials: N
authors.lastname: Goto
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsurumi
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000493:pharmacokinetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000473:pathology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009363:Neoplasm Proteins; D014364:Tryptophan; D003520:Cyclophosphamide; C525396:1-methyltryptophan