A combination of the metabolic enzyme inhibitor APO866 and the immune adjuvant L-1-methyl tryptophan induces additive antitumor activity

作者：Yang Huei Jiun; Yen Meng Chi; Lin Chi Chen; Lin Chiu Mei; Chen Yi Ling; Weng Tzu Yang; Huang Tzu Ting; Wu Chao Liang; Lai Ming Derg^*

来源：Experimental Biology and Medicine, 2010, 235(7): 869-876.

DOI：10.1258/ebm.2010.010001

• indoleamine 2,3-dioxygenase
• 1-methyl tryptophan
• APO866 (FK866, WK175)
• cancer therapy
• combination therapy
• gastric cancer
• bladder cancer

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.

• 出版日期2010-7
• 单位河北医科大学