TY - JOUR
T1 - Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice
AU - Nakamura, Nobuhiko
AU - Hara, Takeshi
AU - Shimizu, Masahito
AU - Mabuchi, Ryoko
AU - Nagano, Junji
AU - Ohno, Tomohiko
AU - Kochi, Takahiro
AU - Kubota, Masaya
AU - Shirakami, Yohei
AU - Goto, Naoe
AU - Ito, Hiroyasu
AU - Saito, Kuniaki
AU - Tanaka, Takuji
AU - Moriwaki, Hisataka
AU - Tsurumi, Hisashi
N1 - Publisher Copyright:
© 2015, The Japanese Society of Hematology.
PY - 2015/9/13
Y1 - 2015/9/13
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84941261772
UR - https://www.scopus.com/pages/publications/84941261772#tab=citedBy
U2 - 10.1007/s12185-015-1835-8
DO - 10.1007/s12185-015-1835-8
M3 - Article
C2 - 26243621
AN - SCOPUS:84941261772
SN - 0925-5710
VL - 102
SP - 327
EP - 334
JO - International Journal of Hematology
JF - International Journal of Hematology
IS - 3
ER -