卡铂或顺铂经动脉灌注化疗晚期非小细胞肺癌的临床观察

目的 探讨卡铂经动脉灌注化疗晚期非小细胞肺癌的临床应用价值.方法 52例经病理学或细胞学证实为晚期非小细胞肺癌的患者,根据灌注化疗药物是否包括卡铂（Carbo）或顺铂（CDDP）分为Carbo组和CDDP组.观察两组经动脉灌注化疗后的疗效及毒副反应,并用x2检验比较两组的疗效及毒副反应差别.结果 52例患者中,Carbo组27例,CDDP组25例.无一例完全缓解.Carbo组部分缓解（PR）15例,稳定8例,进展4例.有效率（PR）为55.6%.CDDP组部分缓解（PR）15例,稳定7例,进展3例.有效率（PR）为60%.二者疗效差别无统计学意义（P＞0.05）.不良反应包括骨髓抑制及胃肠道反应,两组间无统计学差异（P＞0.05）.结论 与顺铂比较,卡铂经动脉灌注给药治疗晚期非小细胞肺癌没有疗效及毒副反应方面的优势.我们主张经动脉灌注化疗非小细胞肺癌仍应选用顺铂作为铂类联合化疗药物.     

多西他赛联合奥沙利铂治疗一线化疗失败的非小细胞肺癌的临床研究

目的观察多西他赛联合奥沙利铂二线治疗晚期非小细胞肺癌（NSCLC）的临床疗效及毒副反应,并进行安全评估。方法52例一线治疗失败的晚期非小细胞肺癌患者采用多西他赛＋奥沙利铂化疗3周期后,用世界卫生组织（WHO）的疗效及抗肿瘤药物急性及亚急性毒性反应分度评价疗效和毒性。结果52例患者均完成3周期以上化疗,完全缓解（CR）4例,部分缓解（PR）12例,总有效率30．8％,不良反应主要表现为骨髓抑制、脱发及消化道反应等,未见水钠潴留。结论多西他赛联合奥沙利铂治疗一线化疗失败的非小细胞肺癌疗效确切,可以提高生活质量,毒副反应较轻,耐受性好,值得临床排一老推广研究．     

An update on biomarkers for kinase inhibitor response in non-small-cell lung cancer

Introduction: The discovery of activating genetic and their use as predictive biomarkers for targeted therapy, such as tyrosine kinase inhibitors (TKIs), has changed the treatment paradigm of non-small cell lung cancer (NSCLC). As a result, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) TKIs have become the standard first-line treatment. Since then, other kinds of targetable oncogenic alterations have been identified in NSCLC. Several novel, molecularly-targeted TKIs have now achieved regulatory approval, while many others are currently in early- or late-phase clinical trial testing. These TKIs have significantly impacted and changed clinical outcomes for advanced NSCLC.

Areas covered: In this review, the authors discuss recent evidence and progress in targeted therapies, especially small molecular tyrosine kinase inhibitors, matched with their biomarkers for the treatment of advanced NSCLC.

Expert commentary: Although targeted therapies dramatically improve the outcome of patients with NSCLC harboring specific oncogenic alterations, molecular and clinical resistance almost invariably develops. New TKIs specifically active in molecular subgroups of NSCLC or the resistance setting have now been developed. The development of additional TKIs and rational combinations may further improve outcomes of NSCLC.     

奥沙利铂对结肠癌细胞DNA损伤修复类抗药基因表达的影响

目的观察奥利沙铂对结肠癌细胞DNA损伤修复类基因表达的影响。方法采用奥利沙铂处理结肠癌细胞株HCT116 48 h。以Western blot免疫印迹法检测奥利沙铂诱导的DNA损伤。采用CCK-8方法探讨奥利沙铂对HCT116细胞生长的影响。采用实时荧光定量PCR(qRT-PCR)方法检测奥利沙铂处理后相关DNA损伤修复基因的表达。结果奥利沙铂处理后,HCT116细胞中DNA损伤标志基因γ-H2AX表达明显上升。DNA损伤切除修复相关基因XPC表达在奥利沙铂处理后出现显著上升,其他DNA损伤修复基因mRNA表达无明显上调。结论 XPC基因可能在临床应用奥沙利铂治疗结肠癌时肿瘤细胞产生抗药性的过程中起到了关键作用。     

血浆DNA在肺癌诊断上的意义

目的研究血浆DNA 3P D3S1300和D3S1289位点杂合性缺失(LOH)作为肿瘤标志物在肺癌诊断中的意义.方法收集初诊69例肺癌患者全血及肿瘤组织,40例非肺癌病人全血,用PCR-银染法分析肿瘤患者血浆、肿瘤组织中及对照组血浆中DNA D3S1300和D3S1289 LOH情况,观察阳性率.结果 69例肺癌患者肿瘤组织DNA中D3S1300和D3S1289的LOH检出率分别为40.6%和31.9%,血浆检出率为29.0%和24.6%.对照组血浆仅有2例DNA检出D3S1300 LOH,3例检出D3S1289 LOH.与肺癌组相比P＜0.01.结论血浆DNA LOH可望作为一种新的肿瘤标志物.     

小细胞肺癌患者循环DNA水平的临床应用

目的研究循环DNA作为肿瘤标志物在小细胞肺癌患者中的临床意义。方法以荧光定量PCR方法检测67例小细胞肺癌（small cell lung cancer,SCLC）患者血浆及柏例健康对照者血浆循环DNA的水平,对比治疗前后的差异及与临床分期的相关性。结果67例SCLC患者Ct值与对照组比较显著降低,差异有统计学意义（P〈0．05）;治疗后SCLC患者各组Ct值与治疗前比较均有增高。差异有统计学意义（P〈0．05）;临床分期晚则Ct值减少,其中广泛期SCLC患者Ct值明显降低。结论血浆循环DNA水平与小细胞肺癌患者的临床分期及治疗疗效具有相关性,是一种简单、有效的肺癌标志物。     

紫杉醇铂二联方案一线治疗晚期非小细胞肺癌的疗效分析

目的评估紫杉醇联合顺铂、卡铂一线治疗非小细胞肺癌的临床疗效及毒副反应。方法 244例晚期非小细胞肺癌患者随机分为观察组和对照组,每组各122例,对照组给予紫杉醇(175 mg/m2第一天)联合顺铂(25 mg/m2第1~3天)化疗;观察组给予紫杉醇(175 mg/m2第一天)联合卡铂(AUC 5第1天),每2周期后评价疗效及不良反应。结果紫杉醇联合顺铂、卡铂治疗晚期非小细胞肺癌的有效率分别为40.9%和24.6%,差异有统计学意义(χ2=0.006,P<0.05)。观察组中位生存期为10.2个月,对照组为10.3个月,两组差异无统计学意义(P>0.05);观察组中位疾病进展时间为4.5个月,对照组为4.7个月,两组差异无统计学意义(P>0.05);观察组的1、2年生存率分别为35.7%和8.8%,对照组为37.2%和9.1%,两组差异无统计学意义(P>0.05)。观察组Ⅲ+Ⅳ度血小板减少发生率明显少于对照组,但Ⅲ+Ⅳ度恶心呕吐发生率明显高于对照组,差异具有统计学意义(P<0.05)。结论紫杉醇联合卡铂比紫杉醇联合顺铂一线治疗晚期非小细胞肺癌近期疗效更优,但远期疗效相似,不良反应有所不同。     

Targeting the microRNA-regulating DNA damage/repair pathways in cancer

Introduction: Maintenance of genome stability requires the integrity of the DNA repair machinery. DNA damage response (DDR) determines cell fate and regulates the expression of microRNAs (miRNAs), which in turn may also regulate important components of the DNA repair machinery.

Areas covered: In this review, we describe the bidirectional connection between miRNAs and DDR and their link with important biological functions such as, DNA repair, cell cycle and apoptosis in cancer. Furthermore, we highlight the potential implications of recent findings on miRNA/DDR in determining chemotherapy response in cancer patients, and the use of these biomarkers for novel potential therapeutic approaches.

Expert opinion: Defects in the DDR and deregulation of miRNAs are important hallmarks of human cancer. A full understanding of the mechanisms underlying the connection between miRNAs and DDR/DNA repair pathways will positively impact our knowledge on human tumor biology and on different responses to distinct drugs. Specific miRNAs interact with distinct DDR components and are promising targets for enhancing the effects of, and/or to overcome the resistance to, conventional chemotherapeutic agents. Finally, the development of innovative tools to deliver miRNA-targeting oligonucleotides may represents novel types of cancer interventions in clinic.     

Prognostic role of multiple abnormal genes in non-small-cell lung cancer

BACKGROUNDNon-small-cell lung cancer (NSCLC) has the highest morbidity and mortality rates among all malignant tumor types. Although therapies targeting the mutated genes such as KRAS have been used in the clinic for many years, the prognosis remains poor. Therefore, it is necessary to further study the aberrant expression or mutation of non-target genes affecting the survival and prognosis.AIMTo explore the impact of simultaneous abnormalities of multiple genes on the prognosis and survival of patients.METHODSWe used R packages to analyze gene expression data and clinical data downloaded from The Cancer Genome Atlas (TCGA) database. We also collected samples from 85 NSCLC patients from the First People’s Hospital of Jingzhou City and retrospectively followed the patients. Multivariate Cox regression analysis and survival analysis were performed.RESULTSAnalysis of gene expression data from TCGA revealed that the overexpression of the following single genes affected overall survival: TP53 (P = 0.79), PTEN (P = 0.94), RB1 (P = 0.49), CTNNB1 (P = 0.24), STK11 (P = 0.32), and PIK3CA (P = 0.013). However, the probability of multiple genes (TP53, PTEN, RB1, and STK11) affecting survival was 0.025. Retrospective analysis of clinical data revealed that sex (hazard ratio [HR] = 1.29; [95%CI: 0.64-2.62]), age (HR = 1.05; [95%CI: 1.02-1.07]), smoking status (HR = 2.26; [95%CI: 1.16-4.39]), tumor histology (HR = 0.58; [95%CI: 0.30-1.11]), cancer stage (HR = 16.63; [95%CI: 4.8-57.63]), epidermal growth factor receptor (EGFR) mutation (HR = 1.82; [95%CI: 1.05-3.16]), abundance (HR = 4.95; [95%CI: 0.78-31.36]), and treatment with tyrosine kinase inhibitors (TKIs) (HR = 0.58; [95%CI: 0.43-0.78]) affected patient survival. Co-occurring mutations of TP53, PTEN, RB1, and STK11 did not significantly affect the overall survival of patients receiving chemotherapy (P = 0.96) but significantly affected the overall survival of patients receiving TKIs (P = 0.045).CONCLUSIONCo-occurring mutation or overexpression of different genes has different effects on the overall survival and prognosis of NSCLC patients. Combined with TKI treatment, the co-occurring mutation of some genes may have a synergistic effect on the survival and prognosis of NSCLC patients.     

血浆DNA定量检测在晚期肺癌患者个体化治疗中的应用

目的通过监测晚期肺癌患者化疗过程中血浆DNA水平的变化,探讨其在疗效预测以及个体化治疗中的应用。方法采集35名晚期肺癌患者化疗前、后静脉血,用磁珠法提取血浆循环DNA和内参照质粒DNA,双重荧光定量PCR技术进行DNA定量检测,以100名体检健康者为对照。结果晚期肺癌患者化疗前血浆DNA平均含量为66.4(33.1~105.0)ng/ml,显著高于健康对照组血浆DNA平均含量22.4(16.2~30.0)ng/ml(P<0.01)。一线药物化疗后,部分缓解组肺癌患者血浆DNA值较化疗前显著下降(P<0.01),且与病情稳定组、病情进展组患者血浆DNA值有显著差异(P均<0.05),而与健康对照组已无差异。生存曲线分析显示,化疗后血浆DNA<50 ng/ml的患者生存率高于血浆DNA≥50 ng/ml的患者(P<0.01)。结论血浆DNA的变化可敏感地反映晚期肺癌患者化疗疗效,在肿瘤个体化治疗中发挥重要作用。     

血浆循环游离DNA浓度及完整性对肺癌和肺结核鉴别诊断的价值

目的用实时荧光定量PCR(RT-PCR)检测肺癌、肺结核患者及健康人血浆循环游离DNA(cf-DNA)浓度及完整性,探讨其对肺癌和肺结核鉴别诊断的价值。方法收集49例肺结核患者、46例肺癌患者和47例健康对照者静脉血标本。用RT-PCR技术定量检测各组血浆cf-DNA中ALU115和ALU247浓度及完整性(ALU115/ALU247),化学发光微粒子免疫分析技术检测血浆糖链抗原(CA125)浓度;用Kruskal-Wallis H非参数检验比较总体差异,用Mann-Whitney U检验进行两两比较;绘制ROC曲线评价各项指标的诊断效能。结果肺结核组、肺癌组和健康人对照组间血浆cf-DNA中ALU115浓度(K-Wχ2=96.716,P=0.000)、ALU247浓度(K-Wχ2=25.228,P=0.000)、血浆cf-DNA完整性(K-Wχ2=75.283,P=0.000)差异均有统计学意义;肺结核患者较健康对照者血浆cf-DNA ALU115浓度(Z=-6.754,P=0.000)、ALU247浓度(Z=-4.570,P=0.000)和cf-DNA完整性(Z=-2.950,P=0.000)均升高;肺癌患者较健康对照者血浆cf-DNA ALU115浓度(Z=-8.245,P=0.000),ALU247浓度(Z=-4.088,P=0.000)和cf-DNA完整性(Z=-7.753,P=0.000)亦有明显升高;肺癌组较肺结核组血浆cf-DNA ALU115浓度(Z=-6.192,P=0.000)和cf-DNA完整性(Z=-7.753,P=0.000)均明显升高。肺癌组血浆cf-DNA ALU115浓度和cf-DNA完整性(ALU115/ALU247)的ROC曲线下面积(AUCROC)、敏感性、特异性分别0.931和0.934、100%和87%、72.9%和90.6%,均高于CA125(0.739,60.9%,86.5%),而ALU247(0.610,43.5%,79.2%)均低于CA125。结论RT-PCR检测血浆cf-DNA中ALU115和ALU247浓度及完整性可作为肺癌和肺结核辅助诊断的分子生物学指标。     

循环肿瘤DNA检测在非小细胞肺癌早期预警及监测管理中的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌的85%,发病率和病死率位居全球前列,由于其起病与进展的隐匿性,被发现时患者已丧失最佳的治疗时机。国内外课题组致力于NSCLC早期检测技术的研发及精准化治疗方法学的探寻,以期延长患者的无进展生存期和总存活时间。液体活检即通过血液、尿液或唾液等进行疾病特异性生物学标志物检测,具有微创性、高敏感性、可重复性等优势。该手段有助于癌症基因图谱的全面反映,极大克服了病灶组织学活检在时空上的异质性,对耐药靶点的发现、新药疗效预测及临床用药方案的调整意义深远。本文就液体活检中的环肿瘤DNA(circulating tumor DNA,ctDNA)检测在NSCLC早期诊断及监测管理的研究进展进行综述,以促进该技术临床应用价值的开拓。     

顺铂联合多西他赛治疗非小细胞型肺癌的效果观察

目的探讨顺铂联合多西他赛治疗非小细胞型肺癌的效果。方法分析收治的非小细胞型肺癌患者临床资料,分为对照组25例（采用普通的化疗方案）和观察组（顺铂联合多西他赛治疗组）50例,观察两组非小细胞肺癌患者生活质量评分和远期生存率情况。结果观察组非小细胞肺癌患者的生活质量评分和远期生存率均明显高于对照组,差异均有统计学意义（P〈0．05）。结论顺铂联合多西他赛治疗非小细胞型肺癌临床效果明显,生存率良好。     

吉西他滨联合卡铂治疗高龄晚期非小细胞肺癌的临床观察

目的 观察吉西他滨联合卡铂治疗高龄晚期非小细胞肺癌(NSCLC)的疗效及毒副作用.方法 30例晚期非小细胞肺癌患者给予吉西他滨与卡铂联合治疗,吉西他滨1 000 mg/m2,静滴,第1、8天,卡铂AUC 5,静滴,第1天.28天为一周期,每例患者治疗2周期以上.两个治疗周期后评价疗效和毒性,并随访评判缓解期及生存期.结果 全组完全缓解1例,部分缓解13例,稳定13例,进展3例,总有效率为46.7%.初治组有效率为47.1%,复治组为46.2%.两组有效率无显著性差异(P＞0.05).中位生存期10.6个月(7～23个月),1年生存率46.0%.生存质量(KPS评分)改善19例(63.3%),稳定8例(26.7%),下降3例(10.0%).最常见的毒副作用为骨髓抑制,Ⅲ～Ⅳ度白细胞和血小板下降发生率分别为30.0%和26.7%,其余毒副作用均轻微,可耐受.结论 吉西他滨联合卡铂治疗高龄晚期非小细胞肺癌患者疗效较好,主要毒性为血液学毒性,辅以重组人粒细胞集落刺激因子(rhG-CSF)、重组人白介素-11(rhIL-11)以及免疫和营养支持治疗,可以顺利完成化疗.吉西他滨联合卡铂可作为高龄晚期非小细胞肺癌患者的一线治疗方案.     

A novel histone deacetylase (HDAC) inhibitor MHY219 induces apoptosis via up-regulation of androgen receptor expression in human prostate cancer cells

Histone deacetylase (HDAC) inhibitors are a new class of anticancer agents that act by inhibiting cancer cell proliferation and inducing apoptosis in various cancer cell lines. To investigate the anticancer effect of a novel histone deacetylase (HDAC) inhibitor MHY219, its efficacy was compared to that of suberoylanilide hydroxamic acid (SAHA) in human prostate cancer cells. The anticancer effects of MHY219 on cell viability, HDAC enzyme activity, cell cycle regulation, apoptosis and other biological assays were performed. MHY219 was shown to enhance the cytotoxicity on DU145 cells (IC₅₀, 0.36 μM) when compared with LNCaP (IC₅₀, 0.97 μM) and PC3 cells (IC₅₀, 5.12 μM). MHY219 showed a potent inhibition of total HDAC activity when compared with SAHA. MHY219 increased histone H3 hyperacetylation and reduced the expression of class I HDACs (1, 2 and 3) in prostate cancer cells. MHY219 effectively increased the sub-G1 fraction of cells through p21 and p27 dependent pathways in DU145 cells. MHY219 significantly induced a G2/M phase arrest in DU145 and PC3 cells and arrested the cell cycle at G0/G1 phase in LNCaP cells. Furthermore, MHY219 effectively increased apoptosis in DU145 and LNCaP cells, but not PC3 cells, according to Annexin V/PI staining and Western blot analysis. These results indicate that MHY219 is a potent HDAC inhibitor that targets regulating multiple aspects of cancer cell death and might have preclinical value in human prostate cancer chemotherapy, warranting further investigation.     

人核心蛋白聚糖基因靶向肺癌细胞特异性表达载体的构建及其表达

目的构建调控人核心蛋白聚糖基因特异性在肺癌细胞A549内表达的基因表达载体,为进一步应用该基因进行肺癌靶向治疗的研究奠定实验基础。方法应用PCR技术从人外周血基因组中扩增肺癌细胞特异性表达的人分泌型白细胞蛋白酶抑制剂的启动子,利用基因重组技术将该启动子插入真核细胞表达载体pcDNA3.1（＋）,替换该载体的CMV启动子与增强子序列,从而构建成由人分泌型白细胞蛋白酶抑制剂基因的启动子启动基因表达的基因表达载体。将人核心蛋白聚糖基因通过基因重组技术插入到上述载体人分泌型白细胞蛋白酶抑制剂基因启动子的下游。PCR产物通过测序鉴定核苷酸序列。重组载体通过限制性酶切进行鉴定。结果 PCR扩增的人分泌型白细胞蛋白酶抑制剂的启动子片段长度为1 250 bp;该启动子经测序获得的核苷酸序列与Genebank上该基因上游5′末端转录调控区的序列完全一致;重组载体的酶切鉴定结果显示（1）该启动子成功插入到pcDNA3.1（＋）载体,并替换CMV启动子与增强子序列,（2）人核心蛋白聚糖基因成功插入该载体。结论成功构建由人分泌型白细胞蛋白酶抑制剂基因启动子调控人核心蛋白聚糖基因表达载体,该载体实现调控人核心蛋白聚糖基因在肺癌细胞内特异性表达。     

EGFR-TKI联合化疗对晚期非小细胞肺癌患者血清IGF-1和AGR2水平的影响

目的观察表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)联合化疗对非小细胞肺癌(NSCLC)患者化疗前后血清胰岛素样生长因子1(IGF-1)和前梯度蛋白2(AGR2)水平变化的影响,探讨IGF-1和AGR2能否作为评估NSCLC化疗疗效及预后的指标。方法选取68例晚期NSCLC患者给予EGFR-TKI联合化疗为试验组,并以30例健康人群为健康对照组,采用酶联免疫吸附试验(ELISA)分别测定化疗前、化疗3周后血清IGF-1、AGR2水平。采用Kanplan-Meier法分析血清IGF-1、AGR2水平变化对预后的影响。结果(1)EGFR-TKI联合化疗疾病控制率(DCR)为52.9%;(2)试验组治疗前血清IGF-1水平为(329.35±88.13)μg/L,明显高于健康对照组的(146.36±41.27)μg/L(P0.01),试验组治疗前血清AGR2水平为(16.72±6.23)ng/mL,高于健康对照组的(4.38±2.17)ng/mL(P0.01);治疗后血清IGF-1为(211.53±52.31)μg/L、AGR2水平为(9.72±3.56)ng/mL,均比治疗前明显降低(均P0.01);NSCLC患者血清IGF-1与AGR2水平呈正相关(r=0.489,P0.01);(3)治疗有效组患者血清IGF-1水平为(128.62±48.24)μg/L、AGR2水平为(7.22±4.27)ng/mL,分别较治疗前IGF-1[(334.23±82.11)μg/L]、AGR2[(18.43±6.17)ng/mL]明显下降(均P0.01)。Kanplan-Meier分析显示,治疗后血清IGF-1、AGR2水平的高低对预后有明显影响。结论 IGF-1、AGR2水平在评估EGFR-TKI联合化疗对晚期NSCLC的疗效及预后有着潜在的临床价值。     

TP与NP方案全身化疗治疗NSCLC疗效观察

目的研究紫杉醇联合顺铂(TP方案)与长春瑞滨联合顺铂(NP方案)系统化疗治疗中晚期非小细胞肺癌(NSCLC)的疗效观察。方法选择50例NSCLC患者,随机分成2组,每组25例,分别与TP及NP方案治疗,所有患者至少完成2个周期的化疗,评价疗效、生活质量及毒副反应。结果试验组有效率为48%,对照组为44%,试验组略好于对照组。与对照组相比,试验组中位总生存期及中位无进展生存期均无明显统计学差异,不良反应2组亦无明显差异(P>0.05)。结论 TP及NP方案治疗NSCLC,2种化疗方案比较前者略好于后者。     

土贝母含药血清对人肺癌细胞增殖和凋亡的影响

目的 观察土贝母含药血清对人肺癌细胞增殖、凋亡的影响,初步探讨其作用机制.方法 采用灌胃SD大鼠土贝母水提物的方法制备其含药血清.应用不同浓度(0.0％、2.5％、5.0％、10.0％、20.0％、40.0％)含药血清处理人肺癌A549和H1299细胞.采用MTT、免疫荧光法观察含药血清对人肺癌细胞增殖的影响,采用流式...     

Curcumin and Ellagic acid synergistically induce ROS generation,DNA damage,p53 accumulation and apoptosis in HeLa cervical carcinoma cells

Cervical cancer and precancerous lesions of the cervix continue to be a global health issue, and the medication for the treatment for chronic HPV infection so far has not been effective. Potential anticancer and anti HPV activities of two known phytochemicals, Curcumin and Ellagic acid were evaluated in HeLa cervical cancer cells. Curcumin is a natural compound found in the root of Curcuma longa plant and Ellagic acid a polyphenol found in fruits of strawberries, raspberries and walnuts. The combination of Curcumin and Ellagic acid at various concentrations showed better anticancer properties than either of the drug when used alone as evidenced by MTT assay. Besides this, Curcumin and Ellagic acid also restore p53, induce ROS formation and DNA damage. Mechanistic study further indicated that Curcumin and Ellagic acid show anti-HPV activity as evidenced by decrease in the HPV E6 oncoprotein on HeLa cells.