Chen Yung-Che, Lin An-Shen, Hung Yu-Chiang, Chen Kuang-Den, Wu Ching-Yuan, Lie Chien-Hao, Hsiao Chang-Chun, Chen Chung-Jen, Liu Shih-Feng, Fang Wen-Feng, Chang Jen-Chieh, Wang Ting-Ya, Wang Yi-Hsi, Chung Yu-Hsiu, Chao Tung-Ying, Leung Sum-Yee, Su Mao-Chang, Lin Meng-Chih
Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan R.O.C.
Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan R.O.C.
Exp Ther Med. 2017 Sep;14(3):2040-2052. doi: 10.3892/etm.2017.4773. Epub 2017 Jul 11.
It has been demonstrated that the traditional Chinese medicine rikkunshito, ameliorates anorexia in several types of human cancer and attenuates lung injury by inhibiting neutrophil infiltration. The current study investigated the clinical and hematological effects of rikkunshito and its underlying mechanisms of action in the treatment of advanced non-small cell lung cancer (NSCLC). The Illumina microarray BeadChip was used to analyze the whole-genome expression profiles of peripheral blood mononuclear cells in 17 patients with advanced NSCLC. These patients were randomized to receive combination chemotherapy (cisplatin and gemcitabine) with (n=9, CTH+R group) or without (n=8, CTH group) rikkunshito. The primary endpoint was the treatment response and the categories of the scales of anorexia, nausea, vomiting and fatigue; secondary endpoints included the hematological effect and whole genome gene expression changes. The results of the current study indicated that there were no significant differences in clinical outcomes, including treatment response and toxicity events, between the two groups. Median one-year overall survival (OS) was 12 months in the CTH group and 11 months in the CTH+R group (P=0.058 by log-rank test), while old age (>60 years old) was the only independent factor associated with one-year OS (hazard ratio 1.095, 95% confidence interval, 1.09-1.189, P=0.030). Patients in the CTH+R group experienced significantly greater maximum decreases in both white cell count (P=0.034) and absolute neutrophil count (P=0.030) from the baseline. A total of 111 genes associated with neutrophil apoptosis, the cell-killing ability of neutrophils, natural killer cell activation and B cell proliferation were up-regulated following rikkunshito treatment. A total of 48 genes associated with neutrophil migration, coagulation, thrombosis and type I interferon signaling were down-regulated following rikkunshito treatment. Rikkunshito may therefore affect the blood neutrophil count when used with combination chemotherapy in patients with NSCLC, potentially by down-regulating prostaglandin-endoperoxidase synthase 1, , and junctional adhesion molecule 3, while up-regulating elastase, neutrophil expressed, proteinase 3, cathepsin G and cluster of differentiation 24.
已证实，中药六君子汤可改善多种类型人类癌症患者的厌食症状，并通过抑制中性粒细胞浸润减轻肺损伤。本研究调查了六君子汤治疗晚期非小细胞肺癌（NSCLC）的临床和血液学效果及其潜在作用机制。使用Illumina微阵列BeadChip分析17例晚期NSCLC患者外周血单个核细胞的全基因组表达谱。这些患者被随机分为接受联合化疗（顺铂和吉西他滨）加六君子汤（n = 9，CTH + R组）或不加六君子汤（n = 8，CTH组）。主要终点是治疗反应以及厌食、恶心、呕吐和疲劳量表的类别；次要终点包括血液学效果和全基因组基因表达变化。本研究结果表明，两组之间在包括治疗反应和毒性事件在内的临床结局方面无显著差异。CTH组的中位一年总生存期（OS）为12个月；CTH + R组为11个月（对数秩检验P = 0.058），而老年（> 60岁）是与一年总生存期相关的唯一独立因素（风险比1.095，95%置信区间，1.09 - 1.189，P = 0.030）。CTH + R组患者的白细胞计数（P = 0.034）和绝对中性粒细胞计数（P = 0.030）较基线的最大降幅显著更大。六君子汤治疗后，共有111个与中性粒细胞凋亡、中性粒细胞杀伤能力、自然杀伤细胞活化和B细胞增殖相关的基因上调。六君子汤治疗后，共有48个与中性粒细胞迁移、凝血、血栓形成和I型干扰素信号传导相关的基因下调。因此，六君子汤与联合化疗联用时，可能通过下调前列腺素 - 内过氧化物合酶1、 、 和连接黏附分子3，同时上调弹性蛋白酶、中性粒细胞表达的蛋白酶3、组织蛋白酶G和分化簇24，影响NSCLC患者的血液中性粒细胞计数。
