Abstract | OBJECTIVES: Indoleamine-2,3-Dioxygenase (IDO) is an immunosuppressive molecule inducible in various cells. In addition to classic IDO (IDO1), a new variant, IDO2, has recently been described. When expressed in dendritic cells (DCs) or cancer cells, IDO was thought to suppress the immune response to tumors. A novel therapeutic approach in cancer envisages inhibition of IDO with 1-methyl-tryptophan (1MT). The levo- isoform (L-1MT) blocks IDO1, whereas dextro-1MT (D-1MT), which is used in clinical trials, inhibits IDO2. Here we analyze IDO2 expression in human cancer cells and the impact of both 1-MT isoforms on IDO activity. METHODS: Surgically extirpated human primary tumors as well as human cancer cell lines were tested for IDO1 and IDO2 expression by RT-PCR. IDO1 activity of Hela cells was blocked by transfection with IDO1-specific siRNA and analysed for tryptophan degradation by RP-HPLC. The impact of D-1MT and L-1MT on IDO activity of Hela cells and protein isolates of human colon cancer were studied. RESULTS: Human primary gastric, colon and renal cell carcinomas constitutively expressed both, IDO1 and IDO2 mRNA, whereas cancer cells lines had to be induced to by Interferon-gamma (IFN-gamma). Treatment of Hela cells with IDO1-specific siRNA resulted in complete abrogation of tryptophan degradation. Only L-1MT, and not D-1MT, was able to block IDO activity in IFN-gamma-treated Hela cells as well as in protein isolates of primary human colon cancer. CONCLUSIONS: Although IDO2 is expressed in human tumors, tryptophan degradation is entirely provided by IDO1. Importantly, D-1MT does not inhibit the IDO activity of malignant cells. If ongoing clinical studies show a therapeutic effect of D-1MT, this cannot be attributed to inhibition of IDO in tumor cells.
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Authors | Stefan Löb, Alfred Königsrainer, Derek Zieker, Björn L D M Brücher, Hans-Georg Rammensee, Gerhard Opelz, Peter Terness |
Journal | Cancer immunology, immunotherapy : CII
(Cancer Immunol Immunother)
Vol. 58
Issue 1
Pg. 153-7
(Jan 2009)
ISSN: 1432-0851 [Electronic] Germany |
PMID | 18418598
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Indoleamine-Pyrrole 2,3,-Dioxygenase
- RNA, Messenger
- RNA, Small Interfering
- Tryptophan
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Topics |
- Cell Line, Tumor
- Chromatography, High Pressure Liquid
- HeLa Cells
- Humans
- Indoleamine-Pyrrole 2,3,-Dioxygenase
(antagonists & inhibitors, chemistry, genetics, metabolism)
- Neoplasms
(metabolism)
- RNA, Messenger
(biosynthesis)
- RNA, Small Interfering
(genetics)
- Reverse Transcriptase Polymerase Chain Reaction
- Stereoisomerism
- Tryptophan
(analogs & derivatives, chemistry, metabolism, pharmacology)
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