Artikel
Einfluss des IDO2-Blockers D-1MT auf die IDO-Aktivität humaner Tumoren und dendritischer Zellen
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Veröffentlicht: | 23. April 2009 |
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Introduction: Clinical phase-I-trials with cancer patients have been started with the aim of inducing tumor immunity by blocking the immunosuppressive action of indoleamine-2,3-dioxygenase (IDO) with the IDO2-inhibitor dextro-1-methyl-tryptophan (D-1MT). In this study we analyzed IDO2- and IDO1-expression in human dendritic cells (DCs) and tumor cells and further investigated the impact of their respective inhibitors, D-1MT and L-1MT on the abrogation of IDO-activity.
Material and methods: Human mDCs, established tumor cells lines, surgically removed human primary gastric-, colon- and renal cell carcinoma specimens were analyzed for IDO1- and IDO2-expression by RT-PCR. siRNA treatment specific for IDO1 was evaluated by qRT-PCR. IDO-activity was measured and quantified by RP-HPLC.
Results: Human primary tumors investigated in this study constitutively expressed various amounts of IDO1 and IDO2, whereas tumor cell lines and DCs needed to be induced by Interfon-gamma (IFN-γ). Transfection with IDO1-specific siRNA blocked IDO1-transcription in cell lines and DCs. IDO2-expression remained unaffected. Tryptophan breakdown was completely restored upon IDO1-siRNA transfection of tumor cell lines and DCs. Addition of L-1MT, but not D-1MT abrogated IDO-activity of tumor cell lines, DCs and freshly isolated colon carcinoma tumor.
Conclusion: Tumor cells and DCs express IDO2, but in a functionally inactive form. Most importantly, D-1MT does not block their IDO-activity. Therefore, L-1MT is the appropriate candidate for inhibiting IDO.
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