Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer Journal Article
| Authors: | Qian, F.; Villella, J.; Wallace, P. K.; Mhawech-Fauceglia, P.; Tario, J. D. Jr; Andrews, C.; Matsuzaki, J.; Valmori, D.; Ayyoub, M.; Frederick, P. J.; Beck, A.; Liao, J.; Cheney, R.; Moysich, K.; Lele, S.; Shrikant, P.; Old, L. J.; Odunsi, K. |
| Article Title: | Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer |
| Abstract: | It has been reported that levo-1-methyl tryptophan (L-1MT) can block indoleamine-2,3-dioxygenase (IDO) expressed by human dendritic cells (DC), whereas dextro-1-methyl tryptophan (D-1MT) is inefficient. However, whether L-1MT or D-1MT can efficiently reverse IDO-induced arrest of human T-cell proliferation has not been clarified. Here, we show a marked immunosuppressive effect of IDO derived from INDO-transfected 293 cell, IDO<sup>+</sup> ovarian cancer cells, and monocyte-derived DCs on CD4<sup>+</sup> Th1 cells, CD8 <sup>+</sup> T cells, and natural killer cells derived from peripheral blood, ascites, and tumors of ovarian cancer patients. We found that, whereas L-1MT and D/L-1MT can restore proliferation of tumor-derived and peripheral blood T-cell subsets, D-1MT does not effectively restore IDO-induced arrest of T-cell proliferation. Although D-1MT inhibited kynurenine production at high concentrations, L-1MT was more effective in abrogating kynurenine generation and tryptophan depletion, whereas tryptophan was completely depleted by IDO even in the presence of high amounts of D-1MT. Together, the results indicate that, whereas the generation of tryptophan metabolites (kynurenines) by IDO is important in mediating suppression of T-cell proliferation, the degree to which tryptophan depletion is restored by 1MT is also critical in overcoming IDO-induced arrest of T-cell proliferation. ©2009 American Association for Cancer Research. |
| Keywords: | controlled study; human tissue; protein expression; unclassified drug; human cell; ascites; drug efficacy; cancer patient; flow cytometry; lymph nodes; cd8+ t lymphocyte; lymphocyte proliferation; t lymphocyte; ovarian neoplasms; t-lymphocytes; cell division; ovary cancer; dendritic cell; cell line; transfection; lymphocyte activation; kidney; genetic transfection; cancer cell; ovary tumor; cd4+ t lymphocyte; epithelial cells; natural killer cell; immunomodulation; th1 cell; indoleamine 2,3 dioxygenase; monocyte; indoleamine-pyrrole 2,3,-dioxygenase; lymphocytes; t lymphocyte subpopulation; stereoisomerism; tryptophan; tryptophan metabolism; 1 methyltryptophan; dextro 1 methyltryptophan; kynurenine; n methyltryptophan; drug degradation |
| Journal Title: | Cancer Research |
| Volume: | 69 |
| Issue: | 13 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2009-07-01 |
| Start Page: | 5498 |
| End Page: | 5504 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-08-2106 |
| PUBMED: | 19491279 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 12" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus" |
