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.
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