非小细胞肺癌分子靶向治疗药物研究进展

分子靶向药物作为一种新型治疗药物,与传统治疗药物相比具有更强的针对性,可以增强对肿瘤的杀伤力,并减少对正常细胞的毒副作用,现已成为非小细胞肺癌(NSCLC)药物治疗的研究热点。近年来,一些分子靶向药物投入临床应用,其有效性和安全性也得到了进一步证实。本文对近年来NSCLC分子靶向治疗药物的研究进展作一综述。     

非小细胞肺癌新靶向癌基因的研究进展

非小细胞肺癌的靶向治疗已取得较大进展,目前发现较多新的靶向癌基因,包括ROS1、RET、HER-2、FGFR1、BRAF和DDR2基因.该文通过查阅文献,对非小细胞肺癌新靶向癌基因的研究进展进行综述,旨在为临床靶向治疗的研究提供有效依据.     

小细胞肺癌的转化性靶向治疗——莅临突破

小细胞肺癌是高侵袭性疾病,其在所有肺癌的诊断中约占13％.30年来,联合铂类的化学治疗一直是其治疗的主要手段,而放射治疗仅适于局限期患者.由于其肿瘤倍增时间快、播散转移早以及疾病进程中形成药物抵抗的特点,使小细胞肺癌的治疗颇具挑战.目前,新的靶向药物在临床研究中的探索让我们看到些许方向,分子靶向治疗可能成为这一挑战性疾病的最有效疗法.本文综述了这一领域中最新的临床试验结果以及治疗小细胞肺癌的靶向药物.     

空载磁性壳聚糖微球的靶向性研究

药物磁性微球是由超顺磁性纳米磁粒子、抗癌药物和其它成分共同包埋于高分子聚合物载体中构成,它为抗癌药物的靶向性提供了一种新的途径.本文探讨了空载磁性壳聚糖微球(MCMs)的体内分布.将25只家兔分为A组,靶向组;B组,非靶向组;C组,空白对照组;D组,改变磁场加载时间靶向组;E组,改变磁场距离靶向组.检测各组织中Fe的浓度.结果表明靶向组肺组织中分布百分率高于其它各组,磁场距离的改变对Fe在肺组织中的浓度有很大影响,磁场加载时间对其影响较小.     

EGFR靶向药物治疗非小细胞肺癌的研究进展

在世界范围内,肺癌是死亡率最高的恶性肿瘤,其中以非小细胞肺癌(non-small cell lung cancer,NSCLC)为主.近年来,随着人表皮生长因子受体(epidermal growth factor receptor,EGFR)突变体的发现,以吉非替尼(gefitinib)和厄洛替尼(erlotinib)为代表的EGFR酪氨酸激酶抑制剂(EGFR-TKIs)对于携带有EGFR敏感突变的NSCLC具有良好的疗效.然而,耐药问题的出现增加了临床治疗的难度,针对非小细胞肺癌的EGFR靶向治疗,目前仍有很多问题亟待解决.本文现就EGFR靶向治疗的现状与发展进行综述.     

紫杉醇治疗对老年非小细胞肺癌患者生活质量的影响

目的探讨紫杉醇合并放疗方案对老年晚期非小细胞肺癌(NSCLC)患者近期生活质量的影响.方法88例NSCLC患者,按性别、年龄、UICC-TNM分期和细胞病理11配对,分成两组,实验组应用紫杉醇化疗加胸部放疗,对照组应用足叶甙化疗加胸部放疗,治疗前和治疗后第1、3个月分别用肺癌患者生活质量(QOL)评估表测量.结果共配成31对,实验组治疗后1、3个月QOL评分均明显优于对照组(P<0.05),其中前者与肺癌症状和治疗副作用有关的分项评分也明显低于对照组(P<0.05).结论紫杉醇合并放疗方案对NSCLC患者QOL影响优于足叶甙加卡铂放疗方案.     

国产多西紫杉醇治疗晚期非小细胞肺癌的临床研究

目的 探讨国产多西紫杉醇联合顺铂治疗晚期初治非小细胞肺癌的疗效和毒性.方法 经病理细胞学证实的46例晚期非小细胞肺癌患者,采用多西紫杉醇75mg/m2,顺铂75mg/m2,均于dldiv.drop,每3周重复疗程.在多西紫杉醇给药前1d开始口服地塞米松7.5mg,每d2次,连服3d预防过敏.所有患者均接受了两个疗程以上的化疗.结果 完全缓解0例,部分缓解(PR)21例,稳定(SD)19例,进展(PD)6例,总有效率为45.7%.初治24例中PR.14例,有效率58.3%;复治22例中,PR7例,有效率31.8%,两组差异有显著性(P＜0.05).多西紫杉醇主要毒副作用为Ⅱ～Ⅲ度骨髓抑制,Ⅰ～Ⅱ度脱发、乏力和消化道反应,未见严重的过敏反应发生.结论 多西紫杉醇联合顺铂是一种治疗晚期非小细胞肺癌安全有效的化疗方案.     

纳米复合材料GO@AgPt对非小细胞肺癌的放射增敏作用

目的:制备新型纳米复合材料GO@AgPt,探究其对非小细胞肺癌的放射增敏效果。方法:通过改进型的水热法合成纳米复合材料GO@AgPt,通过透射电子显微镜、原子力显微镜、X射线光电子能谱分析、傅里叶红外光谱仪等方法对材料进行形貌及组分分析。应用细胞活性检测试剂盒CCK-8检测材料对肺癌细胞A549和人肺微血管细胞HPMEC的细胞活性的影响;然后通过流式检测及细胞克隆形成实验探究材料对于A549细胞的放射增敏效果。结果:成功制备出粒径大小均匀、化学成分稳定的纳米复合材料GO@AgPt。在一定浓度范围内该材料对肺癌细胞A549有毒性而对正常细胞HPMEC没有明显毒性。该材料能促进癌细胞产生活性氧,与X射线联合作用能促进细胞的凋亡。细胞克隆形成的结果也显示该材料对肺癌细胞具有放射增敏效果。结论:成功制备了纳米复合材料GO@AgPt,证明了该材料对于非小细胞肺癌有明显的放疗增敏效果。     

非小细胞肺癌脑转移靶向治疗及免疫治疗进展北大核心CSCD

非小细胞肺癌(NSCLC)患者常见脑转移,发病率为25%~40%,预后极差且常伴有严重神经功能障碍,未经治疗平均中位生存期仅为1~2个月。靶向治疗和免疫治疗为NSCLC脑转移患者治疗开辟了新的途径,改善脑转移后神经功能障碍,延长中位生存期。本文就NSCLC脑转移靶向治疗及免疫治疗进展进行综述。     

GDNF增强Treg促进非小细胞肺癌细胞增殖和转移的作用研究

为探讨胶质细胞源神经营养因子(glial cell line derived neurotrophic factor,GDNF)增强Treg促非小细胞肺癌(nonsmall cell lung cancer,NSCLC)细胞增殖和转移的作用,分离人外周血中淋巴细胞,用CD4、CD25和Foxp3标记外周血中的Treg;ELISA检测上清中IL-10和TGF-β的水平;EDU实验检测NSCLC细胞的增殖水平;Transwell侵袭实验检测NSCLC细胞的侵袭能力。流式结果显示GDNF能够显著促进淋巴细胞中Treg比例的上升,相对于对照组,低浓度GDNF组Treg的比例增加了6.37倍,相对于低浓度组,高浓度组Treg的比例增加了1.17倍(P0.05);ELISA结果显示GDNF促进Treg分泌IL-10和TGF-β,相对于对照组,低浓度组上清中IL-10和TGF-β的浓度分别增加了4.92倍和4.86倍,相对于低浓度组,高浓度组IL-10和TGF-β的浓度分别增加了108%和119%(P0.05);EDU实验结果显示GDNF能增强Treg促NSCLC细胞增殖作用,相对于Treg组,低浓度和高浓度组NSCLC细胞的增殖率分别上升了77%和144%(P0.05);Transwell实验结果显示GDNF能增强Treg促进NSCLC细胞侵袭的作用,相对于Treg组,低浓度和高浓度GDNF组侵袭细胞的比例分别上升了2.86倍和5.83倍(P0.05);IL-10和TGF-β的阻断均能部分降低GDNF增强Treg促进NSCLC细胞增殖和侵袭的作用(P均0.05)。总之,GDNF能够通过诱导Treg的增殖,进而促进NSCLC细胞增殖和侵袭。     

吉妥辛对吉非替尼耐药性非小细胞肺癌的抑制作用

 目的 在细胞和动物水平评价强心苷药物吉妥辛对耐药性非小细胞肺癌的抑制作用,并对其抑癌的分子机制进行初步探索。方法 吉妥辛和吉非替尼处理H1975细胞后,用MTS法检测细胞的存活率,流式细胞分析法检测细胞的凋亡率;吉妥辛处理移植瘤裸鼠,测量并计算移植瘤体积;吉妥辛处理H1975细胞后,用Western blot检测Erk1/2的磷酸化水平。结果 吉妥辛比吉非替尼更有效地抑制H1975的生长(P＜0.05）,促进其凋亡(P＜0.05）,且能显著抑制裸鼠移植瘤的生长(P＜0.05）。吉妥辛能计量和时间依赖地抑制Erk1/2的磷酸化(P＜0.05）。结论 吉妥辛可作为治疗耐药性非小细胞肺癌的潜在替代药物。     

川陈皮素对非小细胞肺癌A549细胞的抑制作用

目的:观察川陈皮素(5,6,7,8,3′4′-hexamethoxyflavone)对非小细胞肺癌A549细胞的抑制作用并研究其作用机制。方法:以不同浓度的川陈皮素作用于A549细胞,分别用MTT法、细胞生长曲线研究川陈皮素对A549的增殖抑制作用,Giemsa染色观察细胞形态变化。结果:MTT提示川陈皮素浓度为4mg·L-1~128mg·L-1时,对A549的48、72小时抑制率为15%~85%,48小时IC50为25.7mg·L-1,72小时IC50为16.7mg·L-1;生长曲线提示川陈皮素对A549细胞的抑制作用呈明显时效和量效关系;Giemsa染色后细胞出现明显的凋亡形态学变化。结论:川陈皮素对非小细胞肺癌A549细胞具有增殖抑制作用,其机制可能是诱导细胞凋亡。     

Molecular pathology of non-small cell lung cancer

Our increasing understanding of the molecular pathogenesis of non-small cell lung cancer (NSCLC), particularly adenocarcinomas, has opened the door to ‘personalised medicine’ and the advent of new therapeutic strategies. Over the last few years new drugs, or classes of drugs, have been licensed and entered clinical practice for use in advanced NSCLC. The activity of these drugs is dependent on the presence of specific molecular or protein changes in cancer cells which are usually identified using ‘companion diagnostic tests’ specifically designed for this purpose. Pathologists and Pathology Departments have had to forge new links with Clinical Scientists in order to facilitate these additional investigations on the, often limited, tissue obtained for diagnosis. This collaboration plays a critical role in providing the link that allows integration of the traditional morphological diagnosis with the results of these new ‘companion diagnostic’ tests to guide patient management.     

Factors influencing the transfection efficiency of ultra low molecular weight chitosan/hyaluronic acid nanoparticles

The present work describes nanoparticles made of ultra low molecular weight chitosan (ULMWCh)/hyaluronic acid (HA) as novel potential carriers for gene delivery. Small and monodispersed nanoparticles with high in vitro transfection capabilities have been obtained by the complexation of these two polyelectrolytes. ULMWCh (<10 kDa) presents more advantageous characteristics over the higher molecular weight chitosan for clinical applications, namely increased solubility at physiological pH and improved DNA release. The ULMWCh:HA ratio and the HA molecular weights were varied with the aim of obtaining particles in the 100 nm range. Using chitosan (Ch) with a molecular weight of 5 kDa, HA with a molecular weight of 64 kDa, and a weight ratio of 4:1, nanoparticles with a Z-average size of 146 ± 1 nm and narrow size distribution (polydispersity index: 0.073 ± 0.030) were obtained. Nanoparticle images taken in dry conditions by SEM and AFM showed spherical particles. The optimal pH for transfection ranged from 6.4 to 6.8 for 0.25 μg of EGFP plasmid per well, with an incubation time of 4 h. Using these optimized parameters, DNA/ULMWCh:HA nanoparticles successfully transfected 25 ± 1% of the 293T cells with pEGFP, compared to 0.7% obtained for DNA/ULMWCh under the same conditions. This high transfection efficiency of our non-viral gene delivery system could be attributed to the synergic effect of ULMWCh and low charge density of the HA chain for easy release of DNA which makes the system suitable for targeted gene delivery.     

Update on histologic classification of non-small cell lung cancer

Given the recent advances in personalized medicine in lung cancer that are mostly observed in adenocarcinomas, an international multidisciplinary group of lung cancer specialists has recommended a new sub-classification of resected adenocarcinomas, and a histologic classification in small biopsies and cytologic material that constitutes the majority of specimens. Whereas the classification of adenocarcinomas has been shown to have better correlation with prognosis than the current WHO classification, it has brought many questions that need to be addressed. In order to further classify poorly-differentiated NSCLC while preserving tissue for molecular testing in small samples, a minimal 2-marker panel of immunohistochemistry (TTF-1 and 63/p40) has been recommended. In the current WHO classification, squamous cell carcinoma and large cell carcinoma categories include several variants, some of which are based solely on cytomorphologic features and do not appear to have biologic significance. Thus, a new, biology-based sub-classification is also warranted in those categories.     

Platelet linoleic acid is a potential biomarker of advanced non-small cell lung cancer

New parameters that could be used as tumor markers for lung cancer would be valuable. Our aim was to analyze the fatty acid profiles of total lipids from erythrocytes and platelets from patients with advanced non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD) and asthma to reveal the fatty acids that could be used as NSCLC biomarkers. In our study, 50, 15 and 15 patients with advanced NSCLC, COPD and asthma and 50 healthy subjects were enrolled. Fatty acid profiles were investigated using gas chromatography/mass spectrometry followed by ROC (receiver operating characteristics) curves analysis to gain information about biomarkers. Sialic acid (SA) and cytokeratins were measured by the thiobarbituric acid and immunoradiometric methods respectively. Useful fatty acid markers were as follows: erythrocytes, 22:0 and linoleic acid (LA, 18:2n6); platelets, 16:0, 18:0, and LA. At the cutoff value to obtain maximum accuracy, the best biomarker was platelet LA, with higher diagnostic yields than the commonly used markers SA or cytokeratins (100%, 76%, 75% and 86% sensitivity, specificity, positive predictive value and accuracy, respectively). These findings suggest that platelet LA might be used as a biomarker of NSCLC in relation to different aspects of the disease process that now needs to be explored.     

Stathmin在非小细胞肺癌中表达增强* 基金项目：辽宁省科学技术计划立项课题资助（编号：2007225005-13）

 摘要:目的 探讨Stathmin在非小细胞肺癌（non-small cell lung cancer, NSCLC）组织中和正常组织中的表达,了解其与NSCLC临床病理特征之间的关系。方法 用免疫组化与RT-PCR方法,检测43例NSCLC 术后癌组织及正常组织标本中Stathmin蛋白与mRNA的表达。结果 Stathmin蛋白和基因在NSCLC中阳性表达率分别为62.79%和67.44%,显著高于正常组织的16.28%和20.93%（P＜0.01）,其表达与肿瘤细胞分化程度和有无淋巴结转移有关（P ＜0.05）。结论 Stathmin在NSCLC的发生发展过程中起了重要作用,可能成为预测NSCLC恶性程度的新的生物学及个体化治疗的敏感指标。     

Immunotherapeutic targets in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the most common types of cancer in the world and has a 5-year survival rate of ~20%. Immunotherapies have shown promising results leading to durable responses, however, they are only effective for a subset of patients. To determine the best therapeutic approach, a thorough and in-depth profiling of the tumour microenvironment (TME) is required. The TME is a complex network of cell types that form an interconnected network, promoting tumour cell initiation, growth and dissemination. The stroma, immune cells and endothelial cells that comprise the TME generate a plethora of cytotoxic or cytoprotective signalling pathways. In this review, we discuss immunotherapeutic targets in NSCLC tumours and how the TME may influence patients' response to immunotherapy.     

外科治疗非小细胞肺癌280例临床分析

目的探索不同的外科手术切除方式治疗非小细胞癌的安全性和远期疗效。方法选取我院2002年1月至2007年1月手术治疗的280例非小细胞癌患者,其中全肺切除组180例,肺叶袖状切除组100例,将两种手术方式治疗的术后并发症发生率、死亡率以及5年生存率进行比较分析。结果全肺切除后并发症发生率21.1%,袖状切除后并发症发生率10.9%,两组差异有统计学意义（P〈0.05）;全肺切除后死亡率3.9%,袖状切除后死亡率3.0%,两组差异无统计学意义（P〉0.05）;全肺切除5年生存率30.2%,袖状切除44.3%,组间差异有统计学意义（P〈0.05）,其中N0、N1分型患者5年生存率袖状切除优于全肺切除（P〈0.05）,N2型患者5年生存率两组差异无统计学意义（P〉0.05）。两组患者的术后复发率差异无统计学意义（P〉0.05）。结论对非小细胞癌的治疗,采用肺叶袖状切除的总体治疗效果要优于全肺切除术。