吉林大学学报(医学版)  2020, Vol. 46 Issue (01): 108-115     DOI: 10.13481/j.1671-587x.20200119

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李瑞阳, 林芷伊, 李晶, 费晶, 徐丹, 巩平
LI Ruiyang, LIN Zhiyi, LI Jing, FEI Jing, XU Dan, GONG Ping
化疗联合二甲双胍治疗前后非小细胞肺癌患者外周血中IGF-1和mTOR表达变化及其疗效分析
Changes of IGF-1 and mTOR expressions in peripheral blood of patients with non-small cell lung cancer before and after chemotherapy combined with metformin and analysis on their therapeutic effects
吉林大学学报(医学版), 2020, 46(01): 108-115
Journal of Jilin University (Medicine Edition), 2020, 46(01): 108-115
10.13481/j.1671-587x.20200119

文章历史

收稿日期: 2019-03-11
化疗联合二甲双胍治疗前后非小细胞肺癌患者外周血中IGF-1和mTOR表达变化及其疗效分析
李瑞阳 , 林芷伊 , 李晶 , 费晶 , 徐丹 , 巩平     
石河子大学医学院第一附属医院肿瘤内科, 新疆 石河子 832000
[摘要]: 目的 观察化疗联合二甲双胍治疗后非小细胞肺癌(NSCLC)患者外周血中胰岛素样生长因子1(IGF-1)和雷帕霉素靶蛋白(mTOR)的表达变化及临床疗效,并阐明其作用机制。方法 60例NSCLC患者根据采用的治疗方法不同分为化疗组(腺癌和鳞癌各15例,采用单纯化疗)和联合组(腺癌和鳞癌各15例,采用化疗联合二甲双胍治疗)。采用ELISA法和实时荧光定量PCR(QT-PCR)法分别检测2组患者外周血中IGF-1和mTOR水平及mRNA表达水平,应用Pearson单因素分析和多因素Logistic回归分析法分析晚期NSCLC患者治疗的影响因素,综合评估疗效。结果 与化疗组比较,联合组患者治疗后与治疗前外周血中IGF-1和mTOR水平及mRNA表达水平差值均降低(t=-3.207,P=0.003;t=2.414,P=0.019;t=-3.635,P=0.001;t=-3.737,P=0.001)。在腺癌中,与化疗组比较,联合组患者治疗后与治疗前外周血中IGF-1和mTOR水平及mRNA表达水平差值均降低(t=5.270,P < 0.01;t=2.816,P=0.009;t=-2.621,P=0.019;t=4.039,P < 0.01);在鳞癌中,与化疗组比较,联合组患者治疗后与治疗前外周血中IGF-1和mTOR水平及mRNA表达水平差值均降低(t=4.164,P < 0.01;t=2.670,P=0.012;t=-2.621,P < 0.01;t=3.502,P=0.002)。从疾病控制率的层面,联合组患者总有效率(80.0%)明显高于化疗组(53.3%)(P < 0.05)。单因素分析,患者性别、吸烟、肿瘤分期和淋巴结转移与2组患者疗效有关(均P < 0.05);美国东部肿瘤协作组(ECOG)评分和肿瘤分化程度与化疗组患者疗效有关(均P < 0.05),胸腔积液与联合组患者疗效有关(P < 0.05)。多因素分析,吸烟和肿瘤分期是2组患者的独立危险因素(均P < 0.05),吸烟和淋巴结转移是化疗组患者的独立危险因素(均P < 0.05),吸烟、分化程度和胸腔积液是联合组患者的独立危险因素(均P < 0.05)。与化疗组比较,联合组患者骨髓抑制、胃肠道反应、肾毒性和肝脏损害的发生率差异均无统计学意义(P>0.05)。结论 化疗联合二甲双胍治疗NSCLC患者的效果较好,且能降低其不良反应,其机制可能与降低患者外周血中IGF-1和mTOR水平有关。
关键词: 二甲双胍    化学疗法    癌, 非小细胞肺    胰岛素样生长因子1    雷帕霉素靶蛋白    
Changes of IGF-1 and mTOR expressions in peripheral blood of patients with non-small cell lung cancer before and after chemotherapy combined with metformin and analysis on their therapeutic effects
LI Ruiyang , LIN Zhiyi , LI Jing , FEI Jing , XU Dan , GONG Ping     
Department of Oncology, First Affiliated Hospital, College of Medical Sciences, Shihezi University, Shihezi 832000, China
[ABSTRACT]: Objective To observe the expression changes of insulin-like growth factor 1(IGF-1)and mammalian target of rapamycin(mTOR)in the peripheral blood of patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy combined with metformin, and to elucidate its mechanism. Methods Sixty patients with NSCLC were divided into chemotherapy group (15 cases of adenocarcinoma and squamous cell carcinoma, treated with chemotherapy alone) and combination group (15 cases of adenocarcinoma and squamous cell carcinoma, treated with chemotherapy combined with metformin). The expression levels of IGF-1 and mTOR protein and mRNA in peripheral blood of the patients in two groups were detected by ELISA and quantitative real-time PCR(QT-PCR) method. Pearson univariate analysis and multivariate logistic regression analysis were used to analyze the influencing factors of the treatment of patients with advanced NSCLC; the curative effect was comprehensively evaluated. Results Compared with chemotherapy group, the differences of the levels of IGF-1 and mTOR and the mRNA expression levels of IGF-1 and mTOR of the patients in combination group before and after treatment were decreased (t=-3.207, P=0.003; t=2.414, P=0.019; t=-3.635, P=0.001; t=-3.737, P=0.001). In adenocarcinoma, compared with chemotherapy group, the differences the levels of IGF-1 and mTOR and the mRNA expression levels of IGF-1 and mTOR of the patients in combination group before and after treatment were decreased (t=5.270, P < 0.01; t=2.816, P=0.009; t=-2.621, P=0.019; t=4.039, P < 0.01); in squamous cell carcinoma, compared with chemotherapy group, the differences of the levels of IGF-1 and mTOR and the mRNA expression levels of IGF-1 and mTOR in peripheral blood of the patients in combination group before and after treatment were reduced (t=4.164, P < 0.01; t=2.670, P=0.012; t=3.072, P=0.008; t=3.502, P=0.002). From the level of disease control rate, the total effective rate of the patients in combination group (80.0%) was significantly higher than that in chemotherapy group (53.3%) (P < 0.05).The univariate analysis results showed that gender, smoking, tumor stage, and lymph node metastasis were related to the therapeutic effects of the patients in two groups (P < 0.05);the ECOG score and tumor differentiation degree were related to the therapeutic effect of the patients in chemotherapy group (P < 0.05), and pleural effusion was related with the therapeutic effect of the patients in combination group (P < 0.05). The results of multivariate analysis showed that smoking and tumor stage were the independent risk factors of the patients in two groups (P < 0.05), and smoking and lymph node metastasis were the independent risk factors of the patiens in chemotherapy group(P < 0.05); smoking, differentiation, and pleural effusion were the independent risk factors of the patients in combination group (P < 0.05).Compared with chemotherapy group, the incidences of bone marrow suppression, gastrointestinal reactions, nephrotoxicity, and liver damage of the patients in combination group had no significant differences(P>0.05). Conclusion Chemotherapy combined with metformin is more effective in the treatment of the patients with NSCLC and can reduce its adverse reactions, its mechanism may be related to the reduction of IGF-1 and mTOR levels in the peripheral blood of the patients.
KEYWORDS: metformin    chemotherapy    cancer, non-small cell lung    insulin-like growth factor 1    mammalian target of rapamycin    

非小细胞肺癌(non-small cell lung cancer, NSCLC)是近年来发病率和死亡率最高的恶性肿瘤[1]。随着环境及人们生活方式的改变,其发病率和死亡率呈现上升的趋势,多数患者确诊时已到晚期,严重威胁人类健康。目前,临床上对NSCLC患者广泛采取铂类为基础的化疗,铂类化疗药物可以有效延长患者生存时间,提高患者的生存质量,但其不良反应发生率仍居高不下[2]。因此,寻找一种可以提高患者疗效及降低铂类化疗药物对NSCLC患者的不良反应的药物十分必要。近年来,二甲双胍治疗肿瘤已经成为国内外医学研究的重点,其在多种肿瘤的治疗中均发挥作用[3-4]。在乳腺癌细胞系中,二甲双胍已被证明可诱导胰岛素调节的雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)通路底物中特定丝氨酸位点的磷酸化,从而导致细胞凋亡过度增殖[5]。LKHAGVADORJ等[6]研究发现:在肾癌中,胰岛素、胰岛素样生长因子1(insulin-like growth factor 1, IGF-1)和胰岛素样生长因子2(insulin-like growth factor 2, IGF-2)同时触发胰岛素抵抗(insulin resistance, IR)和IGF-1受体(IGF-1R)磷酸化,进而刺激并触发磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3K)-蛋白激酶B(protein kinase B,AKT)-mTOR通路相关基因下调。研究[7]显示:二甲双胍能改善NSCLC并发糖尿病患者预后, 但二甲双胍联合铂类化疗对NSCLC患者的治疗效果却鲜有报道。本研究旨在探讨化疗联合二甲双胍治疗NSCLC的疗效,并探讨其潜在的作用机制,为二甲双胍用于NSCLC患者的临床治疗提供理论依据。

1 资料与方法 1.1 主要试剂和仪器

人IGF-1、mTOR mRNA逆转录试剂盒购自德国ThermoFisher Scientific有限公司,QuantiNova SYBR Green PCR Kit (500)试剂盒购自德国QIAGEN公司,mTOR试剂盒购自上海江莱生物科技有限公司,IGF-1试剂盒购自杭州联科生物技术有限公司。普通96孔PCR仪购自日本TaKaRa公司,4℃离心机、96孔板离心震荡机和7500 Fast Real-Time PCR system机购自德国Therma scientific公司,BIO-TEK全自动酶标仪购自杭州联科生物技术有限公司

1.2 一般资料

选取2017年11月29日—2018年6月20日经石河子大学医学院附属第一医院经病理证实为晚期NSCLC患者60例,由医生根据患者病情、结合患者意见共同商定,选取不同的治疗方式,分为化疗组和联合组,其中30例患者采用单纯化疗(化疗组),30例患者采用化疗联合二甲双胍治疗(联合组)。化疗组30例,其中男性22例,女性8例;年龄32~75岁,中位年龄56岁;吸烟17例,不吸烟13例;腺癌15例,鳞癌15例;Ⅲ期14例,Ⅳ期16例;美国东部肿瘤协作组(ECOG)评分:1分22例,2分8例;中分化21例,低分化9例;周围型24例,中央型6例;淋巴结转移19例,无淋巴结转移11例;远处转移16例,无远处转移14例;胸腔积液7例,无胸腔积液23例。联合组30例,其中男性19例,女性11例;年龄47~74岁,中位年龄58岁;吸烟14例,不吸烟16例;腺癌15例,鳞癌15例;Ⅲ期9例,Ⅳ期21例;ECOG评分:1分24例,2分6例;中分化12例,低分化18例;周围型25例,中央型5例;淋巴结转移22例,无淋巴结转移8例;远处转移20例,无远处转移10例;胸腔积液5例,无胸腔积液25例。2组患者基本资料组间比较差异均无统计学意义(P>0.05),具有可比性。

1.3 纳入标准

① 患者年龄20~75岁;②NSCLC患者的诊断参照人民卫生出版社第8版《外科学》中的诊断标准;③根据国际抗癌联盟(International Union Against cancer,UICC)2017年1月颁布实施的最新版肺癌TNM分期标准进行TNM分期;④无糖尿病史;⑤ECOG功能状态评分0~2分;⑥重要脏器功能基本正常;⑦具有影像学可测量的病灶;⑧病理证实为鳞癌及无表皮生长因子受体(epidermal growth factor receptor, EGFR)基因突变的腺癌。

1.4 排除标准

① 具有明显临床症状的心脏疾病患者,如充血性心衰、症状明显的冠心病、药物难以控制的心律失常及原发性或继发性高血压(血压高于180/110 mmHg),或6个月内曾有心肌梗死发作,或心功能不全的患者;②对化疗方案严重不耐受的患者;③精神障碍者、无法律行为能力者和医学或伦理学原因影响研究继续进行者,现有严重肝脏疾病(肝硬化等)、肾脏疾病和呼吸道疾病等慢性系统性疾病患者;④肺结核患者,人类免疫缺陷病毒(HIV)感染患者, 乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染患者。

1.5 化疗方法

腺癌采用培养曲塞联合铂类化疗(PP)方案,化疗方案为培美曲塞二钠(上海凯茂生物医药有限公司,国药准字H20080210)500 mg·m-2第1天静脉滴注,顺铂75mg·m-2第1天静脉滴注或者注射用卡铂(0.1g/瓶,齐鲁制药有限公司,批号:7F013B01)血药浓度-时间曲线下面积(AUC)5 mg·mL-1·min-1静脉滴入,每21 d重复,共治疗2个周期。鳞癌采用吉西他滨联合铂类化疗(GP)方案,化疗方案为吉西他滨(山西普德药业有限公司,国药准字H20183199)1 g·m-2第1天静脉滴注,顺铂和卡铂具体用药方案同腺癌,每21 d重复,共治疗2个周期。联合组患者在上述化疗方案的基础上,于化疗第1天开始早饭后服二甲双胍0.25 g,每天1次,直至第3个周期化疗前1 d停止。所有患者治疗前于本院行胸部CT检查,检测外周血中IGF-1和mTOR水平及mRNA表达水平,治疗2个周期后复查,观察患者临床疗效及外周血中IGF-1和mTOR水平和mRNA表达水平的变化。本研究临床试验注册号ChiCTR-ONN-17014156,经石河子大学医学院第一附属医院伦理委员会批准,伦理编号:2017-095-02,患者均签署知情同意书。

1.6 疗效评价

参照实体瘤的疗效评价标准1.1版(RECIST1.1)将近期疗效分为完全缓解(complete response,CR)、部分缓解(partial response,PR)、稳定(stable disease,SD)和疾病进展(progressive disease,PD)。CR:可见病灶完全消失,维持1个月以上;PR:肿瘤最大直径和最大垂直直径的乘积缩小≥50%;SD:肿瘤最大直径和最大垂直直径的乘积缩小 < 50%,肿瘤最大直径和最大垂直直径的乘积增大 < 25%;PD:患者出现一个或者多个病灶的肿瘤最大直径和最大垂直直径的乘积增大≥25%。总有效率=(CR+PR+SD)患者例数/患者总例数×100%,至少维持4周。

1.7 ELISA法检测患者外周血中IGF-1和mTOR水平

分别于化疗前和化疗后抽取患者空腹静脉血,室温静置30 min,4 000 r·min-1离心10 min,取上层血清冻存于-80℃冰箱,采用ELISA法检测患者外周血中IGF-1和mTOR水平,各步骤严格按试剂盒说明书进行。

1.8 实时荧光定量PCR(QT-PCR)法检测患者外周血中IGF-1和mTOR mRNA表达水平

引物序列由生工生物工程(上海)股份有限公司设计,引物序列见表 1

表 1 QT-PCR引物序列 Tab. 1 Sequences of QT-PCR primers
Gene Primer sequence (5′-3′)
β-actin F CACGATGGAGGGGCCGGACTCATC R TAAAGACCTCTATGCCAACACAGT
IGF-1 F GCTCTTCAGTTCGTGTGTGGA R GCCTCCTTAGATCACAGCTCC
mTOR F ATGCTTGGAACCGGACCTG R TCTTGACTCATCTCTCGGAGTT

采用Trizol法提取细胞总RNA,定量后反转录为cDNA,特定引物PCR扩增。20 μL反应体系: 2×SYBR Green Master Cmix 10 μL,无酶水5 μL,上下游引物各1 μL,ROX液2 μL,cDNA1 μL。扩增条件: 95℃预变性3min,95℃、30s,60℃、30s,72℃、45s,40个循环,重复测定2次。数据的收集由StratageneMx3000P Real time PCR仪自带软件完成,采用2-ΔΔCT法计算IGF-1和mTOR mRNA表达水平。具体步骤按试剂盒说明书进行。

1.8 统计学分析

采用SPSS22.0统计软件进行统计学分析。患者外周血中IGF-1和mTOR水平及mRNA表达水平以x±s表示,经检验服从正态分布,组间比较采用两独立样本t检验;计数资料用相对数描述,2组患者总有效率及不良反应发生率比较采用χ2检验;多因素分析采用二分类Logistic回归分析;拟合优度检验:①皮尔逊,χ2=2.624,df=4,P=0.623;②偏差,χ2=2.631,df=4,P=0.621。检验水准α=0.05(双侧)。

2 结果 2.1 2组患者治疗前后外周血中IGF-1和mTOR水平差值

联合组患者治疗前后外周血中IGF-1和mTOR水平差值明显低于化疗组(P < 0.05),联合组腺癌和鳞癌患者治疗前后外周血中IGF-1和mTOR水平差值明显低于化疗组(P < 0.05)。见表 2

表 2 2组患者治疗前后外周血中IGF-1和mTOR水平差值 Tab. 2 Differences of levels of IGF-1 and mTOR in serum of patients in two groups before and after treatment  
(x±s)
Group n Difference of level
IGF-1[ρB/(ng·L-1)] mTOR[ρB/μg·L-1)]
Chemotherapy 30 -0.26±2.01 0.73±1.65
  ADA 15 -1.00±2.48 1.11±1.80
  SCC 15 -0.70±2.08 1.02±1.68
Combination 30 -59.35±70.91* -0.20±1.31*
  ADA 15 -93.05±67.61 -0.51±1.32
  SCC 15 -93.94±86.70# -0.42±1.24#
ADA:Adenocarcinoma;SCC:Squamous cell carcinoma;* P < 0.05 vs chemotherapy group; P < 0.05 vs ADA in chemotherapy group; # P < 0.05 vs SCC in chemotherapy group.
2.2 2组患者治疗前后外周血中IGF-1和mTOR mRNA表达水平差值

联合组患者治疗前后外周血中IGF-1和mTOR mRNA表达水平差值明显低于化疗组(P < 0.05),联合组腺癌和鳞癌患者治疗前后外周血中IGF-1和mTOR mRNA表达水平差值明显低于化疗组(P < 0.05)。见表 3

表 3 2组患者治疗前后IGF-1和mTOR mRNA表达水平差值 Tab. 3 Differences of IGF-1 and mTOR mRNA expression levels of patients in two groups before and after treatment 
(x±s)
Group n Difference of expression level
IGF-1 mRNA mTOR mREA
Chemotherapy 30 0.16±3.88 0.05±2.05
  ADA 15 -1.12±1.87 0.55±1.78
  SCC 15 0.25±3.29 0.74±2.54
Combination 30 -2.43±0.45* -1.53±1.08*
  ADA 15 -2.41±0.38 -1.61±1.04
  SCC 15 -2.38±0.38# -1.82±1.26#
ADA:Adenocarcinoma;SCC:Squamous cell carcinoma;* P < 0.05 vs chemotherapy group; P < 0.05 vs ADA in chemotherapy group; # P < 0.05vs SCC in chemotherapy group.
2.3 2组患者临床疗效的单因素和多因素分析

联合组患者中,PR 17例,SD 7例,PD 6例;化疗组患者中,PR 12例,SD 4例,PD 14例; 联合组患者总有效率[80.0%(24/30)]明显高于化疗组[53.3%(16/30)](P < 0.05)。2组患者临床疗效单因素分析:性别、吸烟、肿瘤分期和淋巴结转移与2组患者疗效有关(均P < 0.05),见表 4;ECOG评分和肿瘤分化程度与化疗组患者疗效有关(均P < 0.05),见表 5;胸腔积液与联合组患者疗效有关(P < 0.05),见表 6。二分类Logistic回归分析各因素赋值见表 7;多因素分析结果显示:吸烟和肿瘤分期是2组患者的独立危险因素(均P < 0.05),吸烟和淋巴结转移是化疗组患者的独立危险因素(均P < 0.05),吸烟、肿瘤分化程度和胸腔积液是联合组患者的独立危险因素(均P < 0.05),见表 8

表 4 2组患者临床疗效单因素分析 Tab. 4 Univariate analysis on clinical efficacies of patients in two groups
Item Effective(n=40) Invalid(n=20) χ2 P
Gender
  Male 32 9 7.548 0.006
  Male Female 8 11
Smoking
  Yes 16 15 6.541 0.001
  No 24 5
Clinical stage
  Ⅲ 21 2 10.188 0.001
  Ⅳ 19 18
ECOG score
  1 32 14 0.745 0.519
  2 8 6
Differentiation
  Poor 8 13 11.868 0.001
   Moderate 32 7
Type
  Peripheral 31 18 1.391 0.238
  Central 9 2
Pathology
  SCC 19 11 0.300 0.584
  ADA 21 9
Lymph node metastasis
  Yes 27 14 0.039 0.844
   No 13 6
Distant metastasis
  Yes 25 11 0.313 0.576
   No 15 9
Pleural effusion
  Yes 6 6 0.417 0.519
   No 34 14
SCC:Squamous cell carcinoma;ADA:Adenocarcinoma.
表 5 化疗组患者临床疗效单因素分析 Tab. 5 Univariate analysis on clinical efficacies of patietns in chemotherapy group
Item Effective(n=40) Invalid(n=20) χ2 P
Gender
Male 10 12 2.058 0.226
Female 6 2
Smoking
Yes 7 10 2.330 0.127
No 9 4
Clinical stage
10 4 3.453 0.063
6 10
ECOG score
1 15 7 7.308 0.012
2 1 7
Differentiation
Poor 2 7 5.000 0.046
Moderate 14 7
Type
Peripheral 15 9 4.051 0.072
Central 1 5
Pathology
SCC 9 6 0.536 0.464
ADA 7 8
Lymph node metastasis
Yes 9 10 0.741 0.389
No 7 4
Distant metastasis
Yes 6 10 3.453 0.063
No 10 4
Pleural effusion
Yes 2 5 2.249 0.204
No 14 9
SCC:Squamous cell carcinoma;ADA:Adenocarcinoma.
表 6 联合组患者临床疗效单因素分析 Tab. 6 Univariate analysis on clinical efficacies of patients in combination group
Item Effective(n=40) Invalid(n=20) χ2 P
Gender
  Male 15 4 0.036 0.850
  Female 9 2
Smoking
  Yes 10 4 1.205 0.378
  No 14 2
Clinical stage
  Ⅲ 7 2 0.040 0.842
  Ⅳ 17 4
ECOG score
  1 21 3 4.219 0.075
  2 3 3
Differentiation
  Poor 8 4 2.222 0.184
  Moderate 16 2
Type
  Peripheral 21 4 1.500 0.254
  Central 3 2
Pathology
  SCC 13 2 0.833 0.651
  ADA 11 4
Lymph node metastasis
  Yes 18 4 0.170 0.645
  No 6 2
Distant metastasis
  Yes 16 4 0.000 1.000
  No 8 2
Pleural effusion
  Yes 2 3 6.000 0.041
  No 22 3
SCC:Squamous cell carcinoma;ADA:Adenocarcinoma.
表 7 各因素和赋值 Tab. 7 Various factors and assignment
Factor Variable Assignment instructions
Smoking X1 Yes = 0,No = 1
Clinical stage X2 Ⅳ stage= 0,Ⅲ stage= 1
ECOG score X3 Two score = 0,One score = 1
Differentiation X4 Poor = 0, Moderate = 1
Clinical type X5 Peripheral = 0, Central = 1
Pathology X6 SCC= 0, ADA = 1
Lymph node metastasis X7 Yes = 0,No = 1
Distant metastasis X8 Yes = 0,No = 1
Pleural effusion X9 Yes = 0,No = 1
Efficacy Y No = 0,Yes = 1
SCC:Squamous cell carcinoma;ADA:Adenocarcinoma.
表 8 2组患者临床疗效独立危险因素分析 Tab. 8 Analysis on independent risk factors of clinical efficacies of patients in two groups
Group Item β SE Wald OR 95%CI P
Two groups
Smoking 1.557 0.414 14.172 4.743 2.109-10.667 < 0.01
Clinical stage 1.448 0.303 22.785 4.255 2.348-7.711 < 0.01
Chemotherapy
Smoking 1.738 0.481 13.061 5.684 2.215-14.585 < 0.01
Lymph node metastasis 1.588 0.700 5.418 4.895 1.241-19.304 0.023
Combination
Smoking 2.045 0.807 6.421 7.732 1.589-37.615 0.011
Differentiation 2.182 0.697 9.783 8.861 2.258-34.770 0.002
Pleural effusion 1.581 0.241 42.909 4.861 3.029-7.802 < 0.01
2.4 2组患者不良反应发生率

联合组患者骨髓抑制、胃肠道反应、肾毒性和肝脏损害的发生率分别为13.3%、30.0%、6.7%和3.3%,与化疗组(分别为10.0%、24.0%、3.3%和6.7%)比较差异均无统计学意义(P>0.05)。

3 讨论

肺癌是全球关注的健康问题,NSCLC占肺癌的绝大部分,由于NSCLC早期症状不明显,约有75%的患者在确诊时已经处于中晚期,丧失了最佳的手术时机,导致NSCLC患者的5年生存率较低[8]。目前,铂类化疗是临床上治疗NSCLC的主要方式,尽管化疗药物可有效抑制肿瘤细胞的增殖,但是在杀伤肿瘤细胞的同时也会损伤正常细胞,同时也加重患者的不良反应,因此寻找一种能提高NSCLC患者疗效、不良反应轻微的治疗方法十分重要。IGF-1是一种多功能蛋白肽,在肺癌细胞生长、增殖和分化过程中发挥重要作用[9],mTOR是PI3K/AKT/mTOR信号通路上的关键因子,对恶性肿瘤发生、侵袭、转移和化疗耐药具有重要的影响,其作用主要是促进细胞增殖,抑制细胞凋亡,促进肿瘤血管生成[10]。二甲双胍是一种常见降糖药,其主要作用是降低细胞能量状态,从而激活细胞代谢传感器AMPK,致使胰岛素和IGF-1的血清浓度下降,而IGF-1是癌细胞的强力有丝分裂原,二甲双胍还可能通过直接抑制mTOR的表达,抑制相关信号传导和合成代谢过程[11]。本研究中联合组患者治疗后血清中IGF-1和mTOR水平明显低于化疗组,提示二甲双胍可能通过降低IGF-1和mTOR的表达来抑制肿瘤的生长。

本研究在常规化疗的基础上联合二甲双胍对NSCLC患者进行治疗,结果显示:联合组患者的总有效率(80.0%)明显高于化疗组(53.3%),提示在常规化疗的基础上联合二甲双胍可能对NSCLC患者具有更好的治疗效果。一项255例NSCLC并发糖尿病的患者研究[12]证实:二甲双胍能提高患者的总生存期和无病进展生存期,本研究结果与之相近,但本研究对象为NSCLC非糖尿病患者,研究样本量较少,后续工作中应积累更多的样本资料,进一步证实本研究的结论。

本研究中,单因素分析结果显示:性别、吸烟、肿瘤分期和淋巴结转移与2组患者疗效有关, ECOG评分和分化程度与化疗组患者疗效有关,胸腔积液与联合组患者疗效有关;多因素分析结果显示:吸烟和肿瘤分期是2组患者的独立危险因素,吸烟和淋巴结转移是化疗组患者的独立危险因素,吸烟、肿瘤分化程度和胸腔积液是联合组患者的独立危险因素。关于性别与NSCLC之间的关系,不同学者有不同看法,LUND-IVERSEN等[13]报道:性别对NSCLC患者治疗效果有影响,考虑与雌激素的保护作用有关。本研究中其他各项指标是否为NSCLC患者的独立预后因素与相关研究[14-16]结果一致。吸烟是众所周知的诱发肺部病变及影响疗效的因素[17],NSCLC的高复发率和高转移率与肿瘤分化程度有密切关联,这也对治疗产生了一定的影响[18],与本研究结果中NSCLC分化程度是联合组患者的独立危险因素一致。胸腔积液是NSCLC常见的并发症,其直接影响患者的疗效及预后[19]。但是影响NSCLC疗效的因素很多,仍需要大量临床研究来探寻NSCLC的病因。

铂类药物的不良反应主要为骨髓抑制、胃肠道反应、肾毒性和肝脏毒性,联合组患者骨髓抑制、胃肠道反应、肾毒性和肝脏损害的发生率与化疗组比较差异无统计学意义,且患者均未出现低血糖表现,可见二甲双胍与铂类联合化疗方案与单纯铂类化疗方案的不良反应相当,不会增加药物毒性和不良反应,患者均可耐受。一项针对卵巢癌的研究[20]显示:mTOR通路在铂类化疗药物的耐药机制中发挥作用。研究[21-22]发现:顺铂与IGF-1结合,会加速IGF-1的断裂,抑制蛋白质的合成。结合本研究联合组患者血清IGF-1和mTOR水平明显低于常规化疗组,提示二甲双胍可能通过降低IGF-1和mTOR水平,延缓铂类化疗药物的耐药,增加了NSCLC的疗效。

综上所述,化疗联合二甲双胍治疗NSCLC患者的效果较好,且能降低其不良反应发生率,其机制可能与降低患者血液中IGF-1和mTOR水平有关。

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