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Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice

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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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Acknowledgments

We thank Ms. Chiyoko Sano and Ms. Kanako Yamaoka for their valuable technical assistance.

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Authors and Affiliations

  1. First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    Nobuhiko Nakamura, Takeshi Hara, Masahito Shimizu, Ryoko Mabuchi, Junji Nagano, Tomohiko Ohno, Takahiro Kochi, Masaya Kubota, Yohei Shirakami, Naoe Goto, Hisataka Moriwaki & Hisashi Tsurumi

  2. Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    Hiroyasu Ito

  3. Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Kuniaki Saito

  4. The Tohkai Cytopathology Institute: Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-Uzura, Gifu, 500-8285, Japan

    Takuji Tanaka

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  1. Nobuhiko Nakamura
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  2. Takeshi Hara
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Correspondence to Hisashi Tsurumi.

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Nakamura, N., Hara, T., Shimizu, M. et al. Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. Int J Hematol 102, 327–334 (2015). https://doi.org/10.1007/s12185-015-1835-8

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  • DOI: https://doi.org/10.1007/s12185-015-1835-8

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