非小细胞肺癌顺铂耐药相关基因生物信息学研究

目的：通过分析非小细胞肺癌顺铂敏感株及耐药株的基因芯片表达数据,筛选差异基因及关键通路,构建蛋白相互作用网络,探讨关键集群功能。方法:从GEO数据库获得基因芯片表达数据,利用GEO2R工具筛选差异基因,通过STRING数据库和Cytoscape软件构建蛋白相互作用网络,经DAVID富集得到相关特征基因与信号通路信息。结果：通过芯片分析共获得481个差异表达基因,相比于敏感细胞株,顺铂获得性耐药细胞株中有418个上调基因和63个下调基因。差异基因功能主要富集在piRNA代谢、DNA甲基化修饰、细胞有丝分裂及细胞周期进程等信号通路。蛋白复合物预测得到主要功能集群6个,分别与细胞趋化性、细胞角化性、piRNA代谢过程、细胞因子受体相互作用、细胞因子分泌调节及染色质沉默相关生物进程相关。结论:本研究利用生物信息学方法,发现顺铂耐药细胞株特征基因及信号通路,其中SAA1、KRT5、TDRD9、BCL2A1、CSF1R和HIST1H1A等显著上调基因及其功能集团可能是非小细胞肺癌顺铂耐药的潜在分子机制,为临床精准治疗提供新的理论依据。     

Anti‐tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells

Ataxia telangiectasia and Rad3‐related (ATR) proteins are sensors of DNA damage, which induces homologous recombination (HR)‐dependent repair. ATR is a master regulator of DNA damage repair (DDR), signaling to control DNA replication, DNA repair and apoptosis. Therefore, the ATR pathway might be an attractive target for developing new drugs. This study was designed to investigate the antitumor effects of the ATR inhibitor, AZD6738 and its underlying mechanism in human breast cancer cells. Growth inhibitory effects of AZD6738 against human breast cancer cell lines were studied using a 3‐(4,5‐dimethylthiazol‐2‐yl)?2,5‐diphenyltetrazolium bromide (methyl thiazolyl tetrazolium, MTT) assay. Cell cycle analysis, Western blotting, immunofluorescence and comet assays were also performed to elucidate underlying mechanisms of AZD6738 action. Anti‐proliferative and DDR inhibitory effects of AZD6738 were demonstrated in human breast cancer cell lines. Among 13 cell lines, the IC₅₀ values of nine cell lines were less than 1 μmol/L using MTT assay. Two cell lines, SK‐BR‐3 and BT‐474, were chosen for further evaluation focused on human epidermal growth factor receptor 2 (HER2)‐positive breast cancer cells. Sensitive SK‐BR‐3 but not the less sensitive BT‐474 breast cancer cells showed increased level of apoptosis and S phase arrest and reduced expression levels of phosphorylated check‐point kinase 1 (CHK1) and other repair markers. Decreased functional CHK1 expression induced DNA damage accumulation due to HR inactivation. AZD6738 showed synergistic activity with cisplatin. Understanding the antitumor activity and mechanisms of AZD6738 in HER2‐positive breast cancer cells creates the possibility for future clinical trials targeting DDR in HER2‐positive breast cancer treatment.     

早期非小细胞肺癌预后相关因素分析

早期非小细胞肺癌患者首选手术治疗后，仍有部分出现了局部复发和／或远处转移。筛选出预后差的患者辅以综合治疗显得尤为重要。本文分析了近年来研究的一些早期非小细胞肺癌的预后因素。     

Concurrent gemcitabine and cisplatin combined with 3D conformal radiotherapy for stage III non-small cell lung cancer

Objective  To study the toxicities and efficacy of concurrent gemcitabine plus cisplatin combined with three-dimensional conformal radiotherapy for stage III non-small cell lung cancer (NSCLC). Methods  Thirty-six patients with pathologically diagnosed NSCLC received radiotherapy and concurrent chemotherapy. There were 22 patients with stage IIIa and 14 patients with IIIb. Radiotherapy was given a total of 60–70 Gy in conventional fractionation. Chemotherapy included gemcitabine (600 mg/m²) and cisplatin (20 mg/m²), once per week. Results  Thirty-two patients received a total dose of 60–72 Gy. Two patients received 56 Gy and another two patients received 58 Gy. Thirty-four patients received 4–6 weeks of chemotherapy, while two patients received only 2 weeks of chemotherapy. The overall response rate (CR + PR), complete response rate (CR), partially response rate (PR) were 83.3% (30/36), 11.1% (4/36) and 72.2% (26/36) respectively. The median follow-up duration was 18.4 months. The 1- and 2-year overall survival rates were 77.8% (28/36) and 55.6% (20/36), respectively. Conclusion  Concurrent gemcitabine and cisplatin combined with three-dimensional conformal radiotherapy for stage III non-small cell lung cancer is effective and well tolerated. Lone-term results need further study.     

吉西他滨联合顺铂或卡铂方案一线治疗晚期非小细胞肺癌的疗效和毒性比较

Objective:To compare the efficacy and toxicity between gemdtabine plus cisplatin and plus carboplatin in firstline treatment of advanced non-small call lung cancer (NSCLC).Methods:Gemcitabine 1000 mg/m2 iv,d1,8;cisplatin 75 mg/m2 iv,d1,or 25 mg/m2 iv,d1-3;carboplatin AUC = 5 iv,d1;repeated every 21 days.Results:All 76 cases were available for objective response.Gemcitabine cisplatin (GCis) group:among 33 cases,CR 1 case,PR 13 cases,MR 3 cases,SD 7 cases,PD 9 cases,response rate,disease control rate,time to progress (TTP),median survival time (MST) and 1-,2-year survival rates were 42.42% (14/33),72.73% (24/33),5 months,14 months and 66.67% (22/33),12.12% (4/33),respectively;Gemcitabine carboplatin (GCarb) group:among 43 cases,PR 13 cases,MR 11 cases,SD 7 cases,PD 12 cases,the results while comparing with those of GCis group were 30.23% (13/43),72.09% (31/43),4 months,11 months and 48.84% (21/43),2.33% (1/43),respectively.Among them,only MST between the two groups had significant statistic difference (x2 = 2.45,P = 0.017).Mild to modest myelo-suppression as well as nausea and vomiting were observed.Conclusion:Both GCis and GCarb regimens had active and well-tolerated toxicity for advanced NSCLC.Cisplatin-based chemotherapy yields a substantial effective advantage over carboplatin-based regimens.Therefore,carboplatin and cisplatin are not equal-active and that cisplatin-based doublet regimens should remain the standard first-line therapy for patients with advanced NSCLC with good performance status.     

艾迪注射液对晚期非小细胞肺癌NP方案化疗的影响

Objective:To evaluate the effects of Aidi injection on vinorelbine plus cisplatin(NP) chemotherapy for advanced non-small cell lung cancer(NSCLC).Methods:Ninety eight patients with advanced NSCLC were randomized to receive either NP alone or NP plus Aidi injection every 3 weeks.The primary endpoint was overall survival;secondary endpoints included overall response rate,time to progression,and safety.Results:The median overall survival time was 11.6 months in NP plus Aidi-treated patients and 10.1 months in NP alone-treated ones,and 1-and 2-year survival rates were higher in the former(47% and 22%) than the latter(42% and 15%).The overall response rates in Aidi injection plus NP-treated patients tended to be higher but not statistically significant compared with NP alone-treated ones.The occurrence rates of grades 3 or 4 toxicities,e.g.fatigue,nausea,vomiting,appetite loss,leucopenia,thrombocytopenia and anemia,were lower in Aidi injection plus NP-treated patients than NP alone-treated ones,although not significantly different between them.Conclusion:Aidi injection promotes NP chemotherapeutic effects,reduces the toxicities,and improves the patients' tolerance to chemotherapy as well.It may be an effective adjunct to chemotherapy in patients with NSCLC.     

重组人血管内皮抑素联合多西紫杉醇和顺铂治疗晚期非小细胞肺癌的临床观察

目的观察重组人血管内皮抑素(恩度)联合多西紫杉醇和顺铂方案(TP)治疗晚期非小细胞肺癌(NSCLC)的近期临床疗效和毒副反应。方法经病理学证实的98例ⅢB～Ⅳ期NSCLC患者随机分为试验组52例,对照组46例,试验组接受恩度联合多西紫杉醇和顺铂方案治疗,对照组单用多西紫杉醇和顺铂方案化疗,用药1周期后评价毒副反应,至少完成2周期治疗后评价疗效。结果试验组有效率为50.0%,临床受益率为78.8%;对照组的有效率为30.4%,临床受益率为58.7%,差异有统计学意义(P<0.05)。毒副反应主要有白细胞减少、血小板减少、恶心、呕吐,肝功损害和肌肉关节痛等,两组比较差异无统计学意义(P>0.05)。结论恩度联合多西紫杉醇和顺铂方案一线治疗晚期NSCLC近期疗效优于单用多西紫杉醇和顺铂方案治疗,且未增加化疗的毒副反应,安全性较好,值得临床推广使用和进一步深入观察。     

吉西他滨联合顺铂治疗晚期非小细胞肺癌的临床研究

目的评价吉西他滨(gemcitabine)联合顺铂治疗晚期非小细胞肺癌的疗效及毒副反应。方法选择经病理证实的晚期非小细胞肺癌41例住院患者采用GP方案行静脉化疗，具体为Gemcitabine 1250mg/m^2d1、d8，DDP30mg/m^2d1-d3，21天重复，至少使用2周期以上。结果完全缓解(CR)4．9％(2／41)，部分缓解(PR)43．9％(18／41)，稳定(SD)34．1％(14／41)，进展(PD)17．00k，(7／41)，总有效率(RR)48．80%；肿瘤控制率(CR PR SD)为82．19％；中位缓解期7．1m，中位生存期11m(4．5～20m)；毒副反应以白细胞及血小板下降、消化道反应、乏力为常见，均可耐受，无化疗相关死亡。结论吉西他滨联合顺铂对晚期非小细胞肺癌有较好疗效，毒副反应可以耐受，值得临床推广。     

多西紫杉醇联合顺铂辅助化疗对非小细胞肺癌的疗效及不良反应影响

目的 探究多西紫杉醇联合顺铂辅助化疗对非小细胞肺癌的疗效以及不良反应影响.方法 回顾性分析246例非小细胞肺癌患者的临床资料.按照不同的治疗方式分为对照组和研究组,对照组采用多西紫杉醇治疗,研究组采用多西紫杉醇联合顺铂治疗,对比两组的近期治疗有效率,不良反应发生率以及功能状态改善情况.结果 研究组近期总有效率为51.22%显著高于对照组29.26%(P﹤0.01);两组发生的各项不良反应(如:恶心呕吐、疲乏无力、白细胞减少等)率均无明显差异(P﹥0.05);两组治疗后,功能状态评分均得到显著提高,研究组提高幅度更大(P﹤0.01);两组患者1年、2年生存率的比较均无明显差异(P﹥0.05).结论 多西紫杉醇联合顺铂辅助化疗对非小细胞肺癌的疗效甚佳,并且不会增加不良反应,还可以改善患者的功能状态,具有临床实际应用价值.     

吉西他滨联合顺铂治疗晚期非小细胞肺癌

目的观察吉西他滨联合顺铂治疗晚期非小细胞肺癌的疗效和安全性．方法吉西他滨联合顺铂治疗37例初治的晚期非小细胞肺癌病人。吉西他滨1000mg／m^2,静脉滴注,d1,d8;顺铂30mg／m^2,静脉滴注,d1～3,21d为一周期．每例病人治疗24周期。结果全组37例均可评价疗效,完全缓解者占2．7％（1／37）,部分缓解者占45．9％（17／37）,稳定者占40．6％（15／37）,进展者占10．8％（4／37）,有效率（RR）为48．6％。中位进展时间（TTP）为6．5mo,中位生存期为10．7mo,1年生存率为43．2％（16137）。主要不良反应为血液学毒性,Ⅲ～Ⅳ度白细胞下降者占24.3％（9／37）,Ⅲ度血小板下降者占10．8％（4／37）,无Ⅳ度下降者。恶心呕吐发生率为78.4％,仅2例为毒性反应Ⅲ度。结论吉西他滨联合顺铂治疗晚期非小细胞肺癌有较好的疗效,病人不良反应可以耐受。     

健择联合顺铂治疗晚期非小细胞肺癌疗效观察

目的:评价健择(GEM)联合顺铂(DDP)治疗晚期非小细胞肺癌(NSCLC)的疗效和毒副反应。方法:收集NSCLC患者38例给予GP方案化疗,GEM1000mg/m2iv d1,8;DDP80mg/m2iv d1,28天为一周期,应用2周期后评价疗效。结果:全组有效率46.9%,无CR病例,鳞癌和腺癌有效率分别为44.0%和46.1%,初治、复治有效率分别为46.9%、33.3%,Ⅲ、Ⅳ期有效率为47.6%、41.2%。毒副反应主要为白细胞下降68.4%,其次为消化道症状为42.1%。结论:GP方案治疗NSCLC疗效较好,毒副反应轻。     

国产吉西他滨联合顺铂治疗28例晚期非小细胞肺癌

目的：评价国产吉西他滨（gemcitabine,GEM）联合顺铂方案治疗晚期非小细胞肺癌的疗效和不良反应。方法：对经病理组织学或细胞学证实的28例晚期非小细胞肺癌患者采用GP方案化疗：GEM1000mg/m^2ivdrip第1、8日,DDP30mg/m^2ivdrip第1-3日,21日为1周期。结果：CR0例,PR12例,SD14例,PD2例,总有效率为42.8%,初治、复治各14例,均有6例PR,有效率均为42.8%,不良反应以消化道反应及白细胞、血小板下降为主,均可耐受。结论：国产吉西他滨联合顺铂对晚期非小细胞肺癌有较好疗效,毒副反应可以耐受,可作为一线或二线化疗方案。     

Triplet chemotherapy with vinorelbine,gemcitabine, and cisplatin for advanced non-small cell lung cancer: a phase II study

We conducted a phase II trial of triplet chemotherapy consisting of vinorelbine, gemcitabine, and cisplatin in patients with advanced non-small cell lung cancer to assess its efficacy and toxicity. Thirty-three patients with chemotherapy-naïve stage IIIB disease (n=8), stage IV disease (n=23), or recurrence after surgical resection (n=2) were given intravenous infusions of vinorelbine 25 mg m⁻², gemcitabine 1000 mg m⁻², and cisplatin 40 mg m⁻² on days 1 and 8 at 3-week intervals. There were 16 partial responses, and the objective response rate was 48% (95% confidence interval: 31–66%). The median survival time was 13.5 months (95% confidence interval: 10.6–16.4 months), and the one-year survival rate was 61%. Grade 4 haematologic toxicity consisted of neutropenia in 72% of patients, and febrile neutropenia occurred in 42% of the patients. There was one toxic death, and it was attributed to neutropenic fever and haemoptysis. Autopsy revealed diffuse pulmonary haemorrhage secondary to bacterial abscesses and vasculitis in both lungs. The common nonhaematologic toxicities included grade 2–3 nausea (39%) and vomiting (18%). Triplet chemotherapy containing vinorelbine, gemcitabine, and cisplatin is effective in the treatment of chemo-näive patients with advanced non-small cell lung cancer, but produces unacceptable frequent febrile neutropenia.British Journal of Cancer (2002) 87, 1360–1364. doi:10.1038/sj.bjc.6600658 www.bjcancer.com© 2002 Cancer Research UK     

安素泰联合顺铂方案治疗非小细胞肺癌疗效观察

目的：评价安素泰联合顺铂方案疗效、耐受性和不良反应。方法：安素泰和顺铂联合方案治疗晚期非小细胞的肺癌（NSCLC）26例。化疗方案以顺铂（DPP）75mg／m2静脉滴注，d1；安素泰（ANZATAX）135mg／m^2静脉滴注，d1，每21—28天重复。结果：全组共完成72个周期，有效率42．31％，一年生存率46．15％。常见的不良反应为骨髓抑制，发生率96．13％。其中Ⅰ度19．23％，Ⅱ度57．69％，Ⅲ度15．39％，Ⅳ度3．85％。结论：患者对安素泰和顺铂联合方案耐受良好，不良反应较轻，初步疗效令人满意，值得进一步研究。     

非小细胞肺癌血清miR-191的表达及意义

目的:探讨血清miR-191对非小细胞肺癌（non-small cell lung cancer,NSCLC）的诊断价值及临床特征。方法:采用实时荧光定量PCR技术检测65例非小细胞肺癌患者血清和65例健康人血清中miR-191的表达量,分析血清miR-191的表达与非小细胞肺癌临床病理参数的关系,通过绘制ROC曲线分析其诊断非小细胞肺癌的价值。结果:非小细胞肺癌患者血清miR-191相对表达水平高于正常对照组(P＜0.05),其表达与临床分期、病理类型及淋巴结转移显著相关（P＜0.05）,而与性别、年龄及吸烟史无相关性(P＞0.05);miR-191的ROC曲线下面积AUC=0.951,其诊断非小细胞肺癌的灵敏度为87.3%,特异度为92.3%。结论:血清miR-191测定的诊断性能较高,有望作为诊断非小细胞肺癌的潜在分子标志物。     

Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST)

Background:

The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G).

Methods:

A total of 433 stage IIIB–IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine–cisplatin (GP), gemcitabine–vinorelbine, gemcitabine–ifosfamide-cisplatin or gemcitabine–ifosfamide–vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets.

Results:

For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3–4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3–4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3–4 nausea-vomiting was significantly increased in P-containing regimens.

Conclusions:

This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.     

Using the theory of coevolution to predict protein-protein interactions in non-small cell lung cancer

Systems biology has become an effective approach for understanding the molecular mechanisms underlying the development of lung cancer.In this study,sequences of 100 non-small cell lung cancer (NSCLC)-related proteins were downloaded from the National Center for Biotechnology Information (NCBI) databases.The Theory of Coevolution was then used to build a protein-protein interaction (PPI) network of NSCLC.Adopting the reverse thinking approach,we analyzed the NSCLC proteins one at a time.Fifteen key proteins were identified and categorized into a special protein family F(K),which included Cyclin D1 (CCND1),E-cadherin (CDH1),Cyclin-dependent kinase inhibitor 2A (CDKN2A),chemokine (C-X-C motif) ligand 12 (CXCL12),epidermal growth factor (EGF),epidermal growth factor receptor (EGFR),TNF receptor superfamily,member 6(FAS),FK506 binding protein 12-rapamycin associated protein 1 (FRAP1),O-6-methylguanine-DNA methyltransferase (MGMT),parkinson protein 2,E3 ubiquitin protein ligase (PARK2),phosphatase and tensin homolog (PTEN),calcium channel voltage-dependent alpha 2/delta subunit 2 (CACNA2D2),tubulin beta class I (TUBB),SWI/SNF-related,matrix-associated,actin-dependent regulator of chromatin,subfamily a,member 2 (SMARCA2),and wingless-type MMTV integration site family,member 7A (WNT7A).Seven key nodes of the sub-network were identified,which included PARK2,WNT7A,SMARCA2,FRAP1,CDKN2A,CCND1,and EGFR.The PPI predictions of EGFR-EGF,PARK2-FAS,PTEN-FAS,and CACNA2D2-CDH1 were confirmed experimentally by retrieving the Biological General Repository for Interaction Datasets (BioGRID) and PubMed databases.We proposed that the 7 proteins could serve as potential diagnostic molecular markers for NSCLC.In accordance with the developmental mode of lung cancer established by Sekine et al.,we assumed that the occurrence and development of lung cancer were linked not only to gene loss in the 3p region (WNT7A,3p25) and genetic mutations in the 9p region but also to similar events in the regions of 1p36.2 (FRAP1),6q25.2-q27 (PARK2),and 11q13 (CCND1).Lastly,the invasion or metastasis of lung cancer happened.     

非小细胞肺癌中miRNA-141的表达及临床意义

目的:探讨miRNA-141在非小细胞肺癌中的表达及其与临床病理特征的关系。方法:采用real time-PCR法对54例非小细胞患者,肺癌组织及正常肺组织的miRNA-141表达水平进行定量分析,结果由2-△△CT处理,并分析与临床病理资料的关系。结果:在NSCLC患者肿瘤组织中miRNA-141表达水平明显升高,其表达与临床分期、病理类型显著相关(P<0.05)。而在不同年龄、性别、肿瘤大小、吸烟史患者间差异无统计学意义(P>0.05)。结论:MiRNA-141高表达与非小细胞肺癌的临床分期、病理分型密切相关,miRNA-141有可能作为非小细胞肺癌的重要肿瘤标志物之一。     

Rsf-1在非小细胞肺癌中的表达及意义

目的:分析Rsf-1在非小细胞肺癌中的表达及与临床病理因素的关系.方法:应用Real-time PCR和免疫组化法检测非小细胞肺癌中Rsf-1的mRNA及蛋白表达情况.结果:有84％(21/25)肺癌组织病例中Rsf-1的mRNA含量明显高于对应的正常肺组织(P＜0.001),肿瘤组织中Rsf-1的mRNA平均值是其癌旁正常肺组织均值的2.37倍.免疫组化结果显示68.4％ (67/98)病例存在Rsf-1蛋白过表达,其过表达与肺癌患者的年龄、性别、肿瘤类型、原发肿瘤分级和淋巴结转移等未发现明显的相关性,而与肺癌的低分化和高p-TNM分期呈正相关(P=0.001;P=0.020).结论:肺癌中存在Rsf-1基因的扩增和蛋白的高表达,并与低分化和高p-TNM分期相关.