Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, leading to the production of NAD+ via the kynurenine pathway. The overexpression of IDO in tumors and tumor-draining lymph nodes induces immune tolerance and enhances tumor growth in vivo. 1-methyl-D-Tryptophan is an inhibitor of IDO (IC50 = 7 μM) that is effective in vivo. In mice, 1-methyl-D-tryptophan prevents T-cell anergy triggered by dendritic cells overexpressing IDO. It augments the antitumor and antiviral immunoresponse of CD8+ T-cells and reduces tumor volume in mice with xenografts overexpressing IDO. 1-methyl-D-Tryptophan, in combination with chemotherapy, causes regression of tumors and prolongs survival. Surprisingly, 1-methyl-D-tryptophan induces the expression of IDO in human ovarian carcinoma SKOV3 cells in culture.
1-Methyl-D-tryptophan is used in biological studies to determine the effect of IDO2 enzyme (indoleamine-(2,3)-dioxygenase) activity and IDO2-mediated arrest of human T cell proliferation. It reverses IDO-mediated immune suppression
Indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, leading to the production of NAD+ via the kynurenine pathway. The overexpression of IDO in tumors and tumor-draining lymph nodes induces immune tolerance and enhances tumor growth in vivo. 1-methyl-D-Tryptophan is an inhibitor of IDO (IC50 = 7 μM) that is effective in vivo. In mice, 1-methyl-D-tryptophan prevents T-cell anergy triggered by dendritic cells overexpressing IDO. It augments the antitumor and antiviral immunoresponse of CD8+ T-cells and reduces tumor volume in mice with xenografts overexpressing IDO. 1-methyl-D-Tryptophan, in combination with chemotherapy, causes regression of tumors and prolongs survival. Surprisingly, 1-methyl-D-tryptophan induces the expression of IDO in human ovarian carcinoma SKOV3 cells in culture.
reaction type: solution phase peptide synthesis
The D isomer is more efficacious as an anticancer agent in chemo-immunotherapy regimens using NSC-26271, NSC 125973, or LY 188011, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targets the IDO gene because the antitumor effect of d-1-methyl-tryptophan is completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Oral administration of dl-1-methyl-tryptophan in combination with NSC 125973 can elicit regression of autochthonous breast tumors[1].
1) Hou?et al. (2007),?Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses; Cancer Res.,?67?792
2) Soliman?et al. (2010),?Indoleamine 2,3-dioxygenase: is it an immune suppressor?; Cancer J.,?16?354
3) Friberg?et al. (2002),?Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T-cell mediated rejection; Int. J. Cancer,?101?151
4) Metz?et al. (2012),?IDO inhibits a tryptophan sufficiency signal that stimulates mTOR; Oncoimmunol.,?1?1460
