1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China.
2 School of Public Health and Management, Institute of Toxicology, Binzhou Medical University, Yantai, P.R. China.
Int J Immunopathol Pharmacol. 2017 Sep;30(3):215-226. doi: 10.1177/0394632017714696. Epub 2017 Jun 12.
Indoleamine 2,3-dioxygenase (IDO) is involved in tumor immune escape and resistance to chemotherapy, and is clinically correlated with tumor progression. IDO inhibitors show marginal efficacy as single agents; therefore, combinations of these inhibitors with other therapies hold promise for cancer therapy. The aim of this study was to investigate the synergistic antitumor effects of IDO inhibitor NLG919 in combination with different regimens of paclitaxel in a murine B16-F10 melanoma model. NLG919 increased the cytotoxic activity of paclitaxel toward B16-F10 cells in the presence of pretreatment with interferon (IFN)-γ in vitro. In B16-F10 tumor-bearing mice, NLG919 was uniformly distributed throughout tumors and decreased kynurenine levels and kynurenine/tryptophan ratios in tumors and plasma for 6-12 h. NLG919 suppressed tumor growth in a dose-dependent manner and exhibited maximum efficacy at 100 mg/kg. In combination with different regimens of paclitaxel, NLG919 displayed synergistic antitumor effects, and NLG919 did not increase the side effects of paclitaxel. Within the tumors, the percentage of CD3, CD8, and CD4 T cells and secretion of IFN-γ and interleukin-2 were synergistically increased, whereas the percentage of CD4CD25 regulatory T cells was decreased. NLG919 can potentiate the antitumor efficacy of paclitaxel without increasing its side effects, suggesting that the combination of IDO inhibitor-based immunotherapy with chemotherapy could be a potential strategy for cancer treatment.
吲哚胺 2,3-双加氧酶（IDO）参与肿瘤免疫逃逸和化疗耐药，与肿瘤进展密切相关。IDO 抑制剂作为单一药物的疗效有限；因此，这些抑制剂与其他疗法的联合有望成为癌症治疗的一种策略。本研究旨在探讨 IDO 抑制剂 NLG919 与不同方案紫杉醇联合应用在小鼠 B16-F10 黑色素瘤模型中的协同抗肿瘤作用。在 IFN-γ预处理的情况下，NLG919 在体外增加了紫杉醇对 B16-F10 细胞的细胞毒性作用。在 B16-F10 荷瘤小鼠中，NLG919 均匀分布于肿瘤中，并在 6-12 小时内降低肿瘤和血浆中的犬尿氨酸水平和犬尿氨酸/色氨酸比值。NLG919 以剂量依赖性方式抑制肿瘤生长，在 100mg/kg 时表现出最大疗效。与不同方案的紫杉醇联合应用时，NLG919 显示出协同的抗肿瘤作用，并且 NLG919 并未增加紫杉醇的副作用。在肿瘤内，CD3、CD8 和 CD4 T 细胞的百分比以及 IFN-γ和白细胞介素-2 的分泌协同增加，而 CD4CD25 调节性 T 细胞的百分比降低。NLG919 可以增强紫杉醇的抗肿瘤疗效而不增加其副作用，这表明 IDO 抑制剂为基础的免疫疗法与化疗的联合可能是癌症治疗的一种潜在策略。
