塞来昔布联合化疗对晚期非小细胞肺癌合并慢性阻塞性肺疾病患者的抗炎作用及其机制研究

Anti-inflammatory effect and mechanism of celecoxib combined with chemotherapy in patients with advanced non-small cell lung cancer complicated with chronic obstructive pulmonary disease

摘要:

目的 观察塞来昔布联合化疗是否能够减轻晚期非小细胞肺癌（NSCLC）合并慢性阻塞性肺疾病患者（COPD）患者的全身炎症反应，并探讨其可能机制。方法 选取2021年3月—2022年10月柳州市人民医院收治的45例ⅢB～Ⅳ期NSCLC合并COPD的患者，分为常规剂量组（塞来昔布200 mg，2次/d，第1~5天联合化疗）、小剂量组（塞来昔布200 mg，1次/d，第1~5天联合化疗）及化疗组（单独化疗），每组15例。COPD患者常规治疗方案不变。根据RECIST 1.1标准评估疗效，CTCAE 4.03版评估化疗毒副反应。所有患者治疗前及治疗4周期后取适量外周血，采用酶联免疫吸附试验检测各组外周血上清液IL-6及TNF-α水平，Western blotting检测外周血细胞内PI3K/Akt通路关键蛋白（p-Akt及t-Akt）的表达。治疗前及治疗4周期后检测患者的肺功能。结果 所有患者均顺利完成4周期的治疗，临床评估治疗有效。3组治疗前后肺功能（FEV₁、FEV₁%pred、FEV₁/FVC）比较，差异均无统计学意义（P >0.05）。常规剂量组患者治疗4周期后IL-6及TNF-α水平均低于化疗组（P <0.05），小剂量组与常规剂量组比较，差异无统计学意义（P >0.05）。常规剂量组治疗4周期后外周血细胞内Akt蛋白相对表达量低于化疗组（P <0.05），小剂量组与常规剂量组比较，差异无统计学意义（P >0.05），3组治疗后Akt蛋白相对表达量比较，差异均有统计学意义（P <0.05），小剂量组与常规剂量组比较，差异均无统计学意义（P >0.05）。结论 塞来昔布联合化疗通过抑制PI3K/Akt通路活性减轻晚期NSCLC合并COPD患者的全身炎症反应，并且未增加药物不良反应，对肺功能无明显影响，小剂量塞来昔布与常规剂量塞来昔布无明显差异。

Abstract:

Objective To investigate whether celecoxib combined with chemotherapy can reduce systemic inflammatory response in patients with advanced non-small cell lung cancer (NSCLC) combined with chronic obstructive pulmonary disease (COPD), and to explore the possible mechanism.Methods Forty-five patients with stage ⅢB to Ⅳ NSCLC complicated with COPD were enrolled and divided into conventional dose celecoxib group (15 patients, celecoxib 200mg/Bid d1-5 combined chemotherapy), low-dose celecoxib group (15 patients, celecoxib 200 mg/Qd d1-d5 combined chemotherapy), and chemotherapy group (15 patients, Chemotherapy alone). The usual treatment regimen for COPD patients remains unchanged. The efficacy was evaluated according to RECIST 1.1 standards, and the toxic and side effects of chemotherapy were evaluated by CTCAE version 4.03. Appropriate amounts of peripheral blood were extracted from all patients before treatment and 4 cycles after treatment, and the levels of IL-6 and TNF-α in peripheral blood supernatant of each group were detected by Elisa. The expression of key proteins (p-Akt and t-Akt) in PI3K/Akt pathway in peripheral blood cells was detected by Westerm blotting The lung function of patients was detected before and after 4 cycles of treatment, and statistical analysis was performed by SPSS 22.0.Results All patients successfully completed 4 cycles of treatment, and the clinical evaluation was effective. There were no changes in lung function (FEV₁, FEV₁%pred, FEV₁/FVC) in the three groups before and after treatment. The levels of IL-6 and TNF-α in celecoxib group were significantly lower than those in chemotherapy group after 4 cycles of treatment, and there was no difference between low-dose group and conventional dose group (P > 0.05). After 4 cycles of treatment, the expression level of p-Akt protein in peripheral blood cells of celecoxib group was significantly lower than that of chemotherapy group, and there was no difference between the low-dose group and the conventional dose group. There was no statistical significance in Akt protein expression before and after treatment among all groups (P > 0.05).Conclusions Celecoxib combined with chemotherapy alleviates systemic inflammatory response in advanced NSCLC patients with COPD by inhibiting PI3K/Akt pathway activity, without increasing adverse drug reactions, and has no significant effect on lung function. There is no significant difference between low-dose celecoxib and conventional dose celecoxib.