piperidines and 1-methyltryptophan

Many types of malignant cells have a higher nicotinamide adenine dinucleotide (NAD) turnover rate than normal cells, as well as the ability to escape immune responses. Indoleamine 2,3-dioxygenase (IDO) is reported to be a negative immune regulator. Overexpression of IDO in dendritic cells is observed in tumor-draining lymph nodes. IDO-expressing dendritic cells suppress T-cell activation and promote immune tolerance. The nicotinamide phosphoribosyl transferase (NAMPT) inhibitor APO866 (also called FK866 or WK175) selectively inhibits tumor growth through intracellular NAD depletion. The IDO-specific inhibitor L-1-methyl-tryptophan (L-1MT) activates immune responses and reduces tumor volume in murine tumor models. We combined L-1MT and APO866 treatments and tested their antitumor effects in the murine gastric and bladder tumor models. In immune-competent mice, a combination of APO866 and L-1MT had a better therapeutic effect than did either L-1MT or APO866 alone. The intracellular level of NAD was suppressed by APO866 but not L-1MT. However, an additive inhibitory effect on tumor growth was not observed in tumor-bearing immune-deficient mice. The new strategy of combining a metabolic inhibitor and an immune adjuvant induced a potent therapeutic effect.

Topics: Acrylamides; Animals; Antineoplastic Agents; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Drug Therapy, Combination; Female; Indoleamine-Pyrrole 2,3,-Dioxygenase; Liver Neoplasms, Experimental; Mice; Mice, Inbred C3H; Mice, Inbred ICR; Mice, Inbred NOD; Neoplasms, Experimental; Nicotinamide Phosphoribosyltransferase; Piperidines; Tryptophan; Urinary Bladder Neoplasms