非小细胞肺癌吉西他滨方案化疗相关耐药标志物RRM1的研究进展

化疗是治疗非小细胞肺癌的主要手段,但是由于耐药的存在,使化疗疗效大大降低.研究表明一些基因表达水平是影响某些化疗药物疗效的重要因素.现对非小细胞肺癌常用化疗药物吉西他滨相关耐药标志物RRM1近年来国内外的研究进展做一综述.     

ERCC1、RRM1基因与非小细胞肺癌治疗预后的关系

化疗耐药是影响非小细胞肺癌化疗疗效的重要因素。ERCC1、RRM1基因作为DNA损伤后修复的代表,其表达的强弱是非小细胞肺癌化疗药物顺铂、吉西他滨的主要影响因素。现就非小细胞肺癌化疗药物顺铂、吉西他滨疗效的分子标志物ERCC1、RRM1基因与预后关系作一综述。     

非小细胞肺癌的化学耐药

肿瘤的生物学特征影响化疗的疗效，由于肿瘤的化学耐药，非小细胞肺癌化疗的效力己达最大，但其预后暗淡及生存期有限。本文介绍非小细胞肺癌化疗中常用的药物，卡铂和顺铂及长春瑞宾、紫杉烷类、依立替康、吉西他滨等五组细胞毒性药物的特异性耐药机制。     

非小细胞肺癌化疗药物敏感基因研究进展

非小细胞肺癌化疗药物敏感基因指导下的化疗是以药物遗传学及基因组学为基础,通过检测患者自身的基因表达及变异谱,预测非小细胞肺癌化疗药物的疗效及毒副作用,从而指导临床选择最佳治疗方案,在提高药物疗效、避免化疗药物相关毒副作用方面有重要指导价值.     

EGFR-TKI治疗非小细胞肺癌后继发耐药的治疗进展

表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)是用于化疗失败或复发的晚期非小细胞肺癌的常用药物,疗效良好。然而,几乎所有接受治疗的患者都会出现耐药,尤其是继发耐药后尚无标准治疗方案。化疗和化疗后重新给予EGFR-TKI治疗是主要的措施,应用不可逆EGFR-TKI治疗及EGFR-TKI联合其他靶点药物治疗是继发耐药的发展方向。     

非小细胞肺癌ERCC1基因和β-tubulinⅢ基因的研究进展

非小细胞肺癌(normal cell lung cancer,NSCLC)的发病率和死亡率近年明显增高,在新诊断的患者中,有65%已不能行手术治疗,因此化学治疗(化疗)是治疗非小细胞肺癌的主要手段。但是由于耐药的存在,化疗疗效有效率有限,治疗的有效率仅为20%-40%。近年来随着肿瘤分子生物学的发展,已发现ERCC1、β-tubulinⅢ等基因的表达水平和化疗药物疗效及预后密切相关,并有可能成为预测疗效进行个体化治疗的重要指标。根据基因表达水平及药物敏感情况选择个体化的化疗方案是肿瘤学研究和临床肿瘤化疗的趋势。     

MTT法在非小细胞肺癌优化治疗方案中的应用

目的:通过非小细胞肺癌体外原代细胞的培养,对其常用的化疗药物进行敏感性检测,探讨不同化疗药物之间的敏感性差异,筛选出最佳的化疗药物或联合化疗方案。方法:应用MTT显色分析法测定40例非小细胞肺癌实体瘤标本对9种化疗药物及其组成的联合化疗方案的敏感性或耐药性,并比较结果。结果:非小细胞肺癌化疗敏感性个体差异较大。联合化疗药物的敏感性明显优于单药,P=0.038。各药物平均抑制率由高到低的顺序依次为DDP HCPT>DDP VP16>HCPT>DDP NVB>DDP ADM IFO>ADM>CTX ADM VCR>DDP>NVB>VP16>CBP>IFO>VP16 CBP>VCR>CTX。无论是单药组间比较,还是联合药物组间比较,其敏感性的差异均有显著差异,均P<0.01。结论:体外肿瘤细胞药敏试验对临床肿瘤化疗用药有很强的指导性,并能发现耐药病例。对非小细胞肺癌患者进行化疗时,应尽量选择联合用药方案。     

非小细胞肺癌多药耐药蛋白表达的临床意义

目的:分析非小细胞肺癌(NSCLC)中的多药耐药蛋白表达与临床分期、化疗疗效等的关系,提出临床合理化疗方式.方法:对82例非小细胞肺癌外周血淋巴细胞,通过免疫组化方法检测P170、LRP、GST-π三种多药耐药蛋白的表达,观察化疗疗效.结果:在82例非小细胞肺癌中,P170表达阳性者的化疗有效率为9.8%,P170表达阴性者的化疗有效率为30.05%;LRP表达阳性者的化疗有效率达15.6%,LBP表达阴性者的化疗有效率为42.1%,GST-π化疗有效率达13.6%,GST-π表达阴性者的化疗有效率达40.0%.化疗疗效差别有统计学意义(P<0.05).结论:多药耐药蛋白表达阳性的患者,其化疗疗效差,不宜过度化疗.     

MTT比色分析法检测非小细胞肺癌药物敏感性

选择有效的化疗药物是肿瘤化疗成功的关键，采用常用的９种化疗药物对２５例非小细胞肺癌进行ＭＴＴ法药物敏感试验。在单药使用时，非小细胞肺癌对抗癌药物敏感度由高至低依次为诺维本、丝裂霉素Ｃ、阿霉素、顺铂、鬼臼乙叉甙、卡铂和长春新碱，而对甲氨喋呤和５氟脲嘧啶耐药。此结果为临床个体化化疗方案的制定提供了参考依据     

非小细胞肺癌患者外周血细胞化疗药物敏感性及其临床意义的研究

目的：通过非小细胞肺癌外周血淋巴细胞和粒细胞体外培养,对其常用的化疗药物进行敏感性检测,以筛选出最佳的化疗方案。方法：应用MTT吸光度法测定32例非小细胞肺癌患者外周血标本对临床常用的4种化疗药物及其组成的2个联合化疗方案的敏感性或耐药性,比较其差异。结果：非小细胞肺癌化疗敏感性个体差异较大,联合化疗药物的敏感性明显优于单药。各药物对淋巴细胞和粒细胞的平均抑制率由高到低的顺序一致,各用药方案间比较均存在差异,部分有显著性差异（P〈0.01）。结论：外周血有核细胞体外药敏试验或耐药试验对临床肿瘤化疗用药有一定的预见性和指导性,对非小细胞肺癌患者进行化疗时,应尽量个体化用药并选择联合用药方案。     

DNA切除修复交叉互补基因1、乳腺癌易感基因、核苷酸还原酶1与非小细胞肺癌

 阐述了近年来非小细胞肺癌（NSCLC）化疗敏感性与DNA 切除修复交叉互补基因1 （ERCC1）、乳腺癌易感基因（BRCA1）、核苷酸还原酶1（RRM1）基因表达关系的研究进展，分析3个基因对NSCLC个体化化疗潜在的指导意义     

核苷酸还原酶亚单位M1和内切修复交叉补体1在非小细胞肺癌中的研究进展

核苷酸还原酶亚单位M1（RRM1）属抑癌基因，RRM1可以激发G2期检测点功能，使受损的DNA得以修复或者发生凋亡，并具有抑制细胞侵袭和转移的作用，另外RRM1还可以调节核苷酸还原酶的活性，是抗代谢药吉西他滨作用的靶分子，RRM1高表达的细胞对吉西他滨耐药。内切修复交叉补体1（ERCC1）是细胞内负责修复受损DNA的核苷酸内切修复通路中的限速酶，可以识别和去除铂-DNA附加物而导致细胞对铂类耐药。本文综述RRM1和ERCC1在非小细胞肺癌患者预后和化疗个体化方面的研究进展。     

Expression of RRM1 and RRM2 as a novel prognostic marker in advanced non-small cell lung cancer receiving chemotherapy

The aim of this study was to examine the prognostic value of BRCA1, RRM1, and RRM2 in patients with non-small cell lung cancer (NSCLC) who received adjuvant chemotherapy. A total of 418 patients who underwent curative pulmonary resection were obtained between January 2007 and November 2009. The relative cDNA quantification for BRCA1, RRM1, and RRM2 was conducted using a fluorescence-based, real-time detection method, and β-actin was used as a reference gene. The low expression of RRM1 and RRM2 significantly increased the platinum-based chemotherapy response (For RRM1: odds ratio (OR)?=?2.09, 95 % confidence interval (CI)?=?1.38–3.18; For RRM2: OR?=?1.64, 95 % CI?=?1.09–2.48). The univariate analysis indicated that low expression of RRM1 attained a longer time to progression and overall survival time, with HR (95 % CI) of 0.50 (0.33–0.77) and 0.60 (0.39–0.92), respectively. Similarly, low expression of RRM2 had a longer time to progression and overall survival, with HR (95 % CI) of 0.57 (0.38–0.86) and 0.47 (0.31–0.71), respectively. In conclusion, low expression of RRM1 and RRM2 could be used to predict the treatment response to platinum-based chemotherapy and survival in NSCLC. The RRM1 and RRM2 could substantially contribute to the future design of individualized cancer treatment in NSCLC patients.     

晚期非小细胞肺癌RRM1蛋白表达与吉西他滨联合顺铂化疗疗效的关系

背景与目的核糖核苷酸还原酶M1(ribonucleotide reductase M1,RRM1)的表达水平与肿瘤细胞对吉西他滨耐药密切相关。本研究旨在探讨晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)中RRM1蛋白的表达水平与吉西他滨联合顺铂(GP方案)化疗疗效的关系。方法应用免疫组织化学染色法检测75例晚期NSCLC组织中的RRM1蛋白表达,75例患者均接受GP化疗方案,回顾调查患者的一般特征、治疗反应、疗效评价及生存时间。组间差异采用卡方检验,采用Kaplan-Meier法进行生存分析。结果 RRM1蛋白表达阳性率为38.7%,与患者的性别、年龄、吸烟状态、临床分期及组织病理学类型无明显相关性(P>0.05);RRM1蛋白高表达组的化疗有效率(31.1%)低于低表达组(41.3%),有统计学意义(P=0.005);RRM1高表达组的1年生存率(27.6%)低于低表达组(58.7%),有统计学意义(P=0.009);RRM1蛋白高表达组的中位生存期(10.70个月)低于低表达组(13.30个月),但无统计学差异(P=0.245);RRM1蛋白高表达组的疾病进展时间(3.10个月)低于低表达组(5.11个月),差异有统计学意义(P=0.042)。结论晚期NSCLC患者组织中RRM1蛋白的表达水平与GP方案化疗的疗效及预后密切相关。     

ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine.

BACKGROUND: Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) gene and ribonucleotide reductase M1 (RRM1) gene in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) gene has been recently extensively investigated in non-small-cell lung cancer (NSCLC). DESIGN: Formalin-fixed, paraffin-embedded bronchoscopic/fine needle aspiration biopsies obtained from 70 patients with advanced NSCLC were retrospectively collected to investigate the expression level of ERCC1, RRM1 and EGFR by real-time PCR. Sufficient amounts of messenger RNA (mRNA) were successfully extracted from 61 (87%) specimens, reverse transcribed and amplified with intron-spanning primers. Forty-one patients had stage IV disease and 43 received cisplatin/gemcitabine chemotherapy. RESULTS: A strong correlation between ERCC1 and RRM1 mRNA levels (r(s) = 0.624, P < 0.0001) was found. Median survival time in patients with low ERCC1 was significantly longer (17.3 versus 10.9, P = 0.0032 log-rank test) as well as in patients with low RRM1 (13.9 versus 10.9, P = 0.0390 log-rank test). Concomitant low expression levels of ERCC1 and RRM1 (n = 33) were predictive of a better outcome (14.9 versus 10.0, P = 0.0345 log-rank test). Among cisplatin-treated patients, a low ERCC1 level was highly predictive of a longer survival (23.0 versus 12.4, P = 0.0001 log-rank test). No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression level and survival was found. At multivariate analysis, performance status, response to chemotherapy, presence of weight loss and ERCC1 were independent prognostic factors for survival. CONCLUSIONS: This retrospective study further validates ERCC1 and RRM1 genes as reliable candidates for customized chemotherapy and shows a higher impact on the survival of NSCLC patients treated with cisplatin/gemcitabine for ERCC1. Prospective pharmacogenomic studies represent a research priority in early and advanced NSCLC.     

非小细胞肺癌组织ERCC1和RRM1基因表达及其对预后影响探讨

目的比较非小细胞肺癌（non-small cell lung cancer,NSCLC）患者原发灶与转移淋巴结中切除修复交叉互补基因1（excision repair cross-complementation group1,ERCC1）和核糖核苷酸还原酶M1亚基（ribonucleotidereductase subunit M1,RRM1）表达情况,探讨ERCC1和RRM1表达状态与NSCLC患者治疗效果及预后的关系,为NSCLC患者的合理治疗提供依据。方法选取山东省肿瘤医院外科六病区2008-08-01-2012-08-31行手术切除且术后病理确诊为NSCLCⅡA-ⅢA期的患者106例,所有患者术前均未接受任何针对肿瘤的治疗措施,均釆用免疫组化技术测定组织中ERCC1和RRM1表达状况,术后均采用长春瑞滨联合顺铂（NP方案）进行辅助化疗,并进行临床随访。结果 NSCLC癌组织及转移淋巴结中RRM1阴性表达患者中位无疾病进展时间分别为23.1和24.7个月,显著优于RRM1阳性表达患者的16.4和19.1个月,两组比较差异有统计学意义,P值分别为0.007和0.026;而ERCC1阴性表达患者中位无疾病生存期为17.5个月,与ERCC1阳性表达患者的19.4个月比较,差异无统计学意义,P=0.59。原发灶和淋巴结转移灶中ERCC1和RRM1的表达水平差异无统计学意义,P〉0.05。不同性别、分期及病理类型的NSCLC患者ERCC1及RRM1表达水平差异均无统计学意义,P〉0.05。结论 NSCLC患者癌组织及转移淋巴结中,RRM1基因表达情况可作为NP方案术后辅助化疗预后的重要指标。     

RRM1基因表达水平预测肺癌对吉西他滨耐药性的研究进展

  吉西他滨是重要的嘧啶类抗代谢化疗药物，核苷酸还原酶是该药物的作用靶点之一。研究表明，在多种吉西他滨耐细胞系中RRM1表达水平较高，同时，肿瘤细胞RRM1高表达的NSCLC患者在吉西他滨治疗后生存期相对较短。但外周血中单个核细胞RRM1表达水平与吉西他滨是否相关还需要作进一步研究。     

外泌体非编码RNA在非小细胞肺癌获得性耐药中的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌中最常见的类型,对化疗及靶向药物的获得性耐药严重影响NSCLC患者的生存期,NSCLC获得性耐药机制复杂,确切机制仍不清楚.肿瘤来源或与肿瘤相关的外泌体是参与调控NSCLC获得性耐药的重要机制,可以通过传递核酸、蛋白质等赋予敏感细胞耐...     

Association of GSTP1 and RRM1 Polymorphisms with the Response and Toxicity of Gemcitabine-cisplatin Combination Chemotherapy in Chinese Patients with Non-small Cell Lung Cancer

Background: Previous studies showed that genetic polymorphisms of glutathione S-transferase P1 (GSTP1)were involved in glutathione metabolism and genetic polymorphisms of ribonucleotide reductase (RRM1) werecorrelated with DNA synthesis. Here we explored the effects of these polymorphisms on the chemosensitivityand clinical outcome in Chinese non-small cell lung cancer (NSCLC) patients treated with gemcitabine-cisplatinregimens. Materials and Methods: DNA sequencing was used to evaluate genetic polymorphisms of GSTP1Ile105Val and RRM1 C37A-T524C in 47 NSCLC patients treated with gemcitabine-cisplatin regimens. Clinicalresponse was evaluated according to RECIST criteria after 2 cycles of chemotherapy and toxicity was assessedby 1979 WHO criteria (acute and subacute toxicity graduation criteria in chemotherapeutic agents). Results:There was no statistical significance between sensitive and non-sensitive groups regarding the genotype frequencydistribution of GSTP1 Ile105Val polymorphism (p>0.05). But for RRM1 C37A-T524C genotype, sensitive grouphad higher proportion of high effective genotype than non-sensitive group (p=0.009). And according to the jointdetection of GSTP1 Ile105Val and RRM1 C37A-T524C polymorphisms, the proportion of type A (A/A + higheffective genotype) was significantly higher in sensitive group than in non-sensitive group (p=0.009). Toxicityshowed no correlation with the genotypes between two groups (p>0.05). Conclusions: Compared with singledetection of genetic polymorphisms of GSTP1 Ile105Val or RRM1 C37A-T524C, joint detection of both may bemore helpful for patients with NSCLC to receive gemcitabine-cisplatin regimens as the first-line chemotherapy.Especially, genetic polymorphism of RRM1 is more likely to be used as an important biomarker to predict theresponse and toxicity of gemcitabine-cisplatin combination chemotherapy in NSCLC.