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: Nobuhiko Nakamura, Takeshi Hara, Masahito Shimizu, Ryoko Mabuchi, Junji Nagano, Tomohiko Ohno, Takahiro Kochi, Masaya Kubota, Yohei Shirakami, Naoe Goto, Hiroyasu Ito, Kuniaki Saito, Takuji Tanaka, Hisataka Moriwaki, Hisashi Tsurumi
• Journal: International journal of hematology (Int J Hematol) Vol. 102 Issue 3 Pg. 327-34 (Sep 2015) ISSN: 1865-3774 [Electronic] Japan
• PMID: 26243621 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• IDO1 protein, mouse
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Neoplasm Proteins
• Tryptophan
• Cyclophosphamide
• 1-methyltryptophan

Topics

• Animals
• Cyclophosphamide (pharmacokinetics, pharmacology)
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, biosynthesis)
• Lymphoma, Non-Hodgkin (drug therapy, enzymology)
• Mice
• Mice, Inbred BALB C
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis)
• Neoplasms, Experimental (drug therapy, enzymology)
• T-Lymphocytes, Regulatory (enzymology, pathology)
• Tryptophan (analogs & derivatives, pharmacokinetics, pharmacology)