吉非替尼和厄洛替尼耐药机制

吉非替尼和厄洛替尼是首批用于晚期非小细胞肺癌(NSCLC)的分子靶向药物,尽管治疗效果显著,但最终多数患者均会发生耐药.近年来研究表明,其耐药机制与表皮生长因子受体(EGFR)二次突变、其他酪氨酸激酶家族受体异常活化及信号通路成分或调节因子基因表达的改变等有关.另有研究表明,可能与EGFR受体内化及肿瘤微环境改变也有相关性.进一步研究其耐药机制,并寻找克服或逆转耐药的方法、开发新的靶向药物已成为肺癌治疗领域的前沿课题.     

阿帕替尼对比替吉奥治疗进展期胃癌疗效和安全性的Meta分析

目的 系统评价阿帕替尼对比替吉奥二线及二线以上治疗进展期胃癌的疗效和安全性,为临床用药提供参考。方法 计算机检索Cochrane图书馆、Pubmed、中国知网（CNKI）和万方医学网自建库至2017年12月的全部文献,收集阿帕替尼与替吉奥二线及二线以上治疗进展期胃癌的随机对照试验,按照修改后的Jadad评分量表评价纳入研究文献质量,提取纳入文献的相关资料,采用Rev Man 5.3版统计软件进行Meta分析。结果 共纳入8项随机对照研究,合计456例患者。Meta分析结果 显示,与替吉奥比较,阿帕替尼能显著提高客观缓解率,差异有统计学意义（RD=0.12,95％CI：0.03～0.20,P=0.008）;阿帕替尼和替吉奥在疾病控制率（RD=0.05,95％CI：-0.03～0.13,P =0.23）和生活质量改善方面（RD=0.11,95％CI：-0.00～0.22,P =0.22）的差异无统计学意义。安全性方面,阿帕替尼组高血压的发生率显著高于替吉奥组（OR=15.27,95％CI：2.79～83.76,P =0.002）,恶心呕吐的发生率显著低于替吉奥组（OR=0.38,95％CI：0.18～0.82,P =0.01）,两组中性粒细胞减少、蛋白尿、手足综合征等其他不良反应发生率的差异均无统计学意义。结论 阿帕替尼二线及二线以上治疗进展期胃癌较替吉奥能更好地提高客观缓解率,且两药不良反应相当。     

阿帕替尼对比替吉奥治疗进展期胃癌疗效和安全性的Meta分析

目的 系统评价阿帕替尼对比替吉奥二线及二线以上治疗进展期胃癌的疗效和安全性,为临床用药提供参考。方法 计算机检索Cochrane图书馆、Pubmed、中国知网（CNKI）和万方医学网自建库至2017年12月的全部文献,收集阿帕替尼与替吉奥二线及二线以上治疗进展期胃癌的随机对照试验,按照修改后的Jadad评分量表评价纳入研究文献质量,提取纳入文献的相关资料,采用Rev Man 5.3版统计软件进行Meta分析。结果 共纳入8项随机对照研究,合计456例患者。Meta分析结果 显示,与替吉奥比较,阿帕替尼能显著提高客观缓解率,差异有统计学意义（RD=0.12,95％CI：0.03～0.20,P=0.008）;阿帕替尼和替吉奥在疾病控制率（RD=0.05,95％CI：-0.03～0.13,P =0.23）和生活质量改善方面（RD=0.11,95％CI：-0.00～0.22,P =0.22）的差异无统计学意义。安全性方面,阿帕替尼组高血压的发生率显著高于替吉奥组（OR=15.27,95％CI：2.79～83.76,P =0.002）,恶心呕吐的发生率显著低于替吉奥组（OR=0.38,95％CI：0.18～0.82,P =0.01）,两组中性粒细胞减少、蛋白尿、手足综合征等其他不良反应发生率的差异均无统计学意义。结论 阿帕替尼二线及二线以上治疗进展期胃癌较替吉奥能更好地提高客观缓解率,且两药不良反应相当。     

非小细胞肺癌脑转移厄洛替尼和吉非替尼治疗临床比较

目的比较和评价厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效。方法回顾性分析2009-01-01-2012-11-25广州医科大学附属第一医院81例晚期NSCLC初诊有脑转移患者和111例晚期NSCLC初诊无脑转移患者,192例患者均为肺腺癌合并EGFR基因突变,分为吉非替尼和厄洛替尼治疗组,生存分析采用Kaplan-Meier法统计,组间生存率比较采用Log-rank检验。结果初诊有脑转移患者颅内病灶,客观有效率为45.68%(37/81),疾病控制率为90.12%(73/81)。吉非替尼、厄洛替尼治疗的无进展生存期(progression-free survival,PFS)分别为9.5和9.0个月,P=0.344;不同EGFR突变类型(19外显子序列缺失突变、21外显子突变)PFS比较分别为10.4和8.6个月,P=0.408。初诊无脑转移患者PFS分别为14.0和15.0个月,P=0.369;不同EGFR突变类型的PFS分别为14.0和15.0个月,P=0.408。结论厄洛替尼和吉非替尼一线治疗肺癌EGFR突变脑转移效果无显著性差异。     

氟马替尼与伊马替尼治疗初诊慢性粒细胞白血病的有效性和安全性比较

目的：比较氟马替尼与伊马替尼治疗初诊慢性粒细胞白血病（CML）的有效性和安全性。方法采用多中心、随机、阳性药物平行对照的研究方法,对24例符合条件的初诊费城染色体阳性 CML慢性期（Ph+ CML-CP）患者给予6个周期（24周）的氟马替尼400 mg／d、600 mg／d 和伊马替尼治疗,分别在给药前及给药后2、4、6、8、10、12、16、20、24周进行血液学评价,给药前及给药后12、24周进行形态学、细胞遗传学和分子生物学评价。结果在有效性方面,治疗6个周期,氟马替尼600 mg／d 组的主要分子学缓解（MMR）率高于伊马替尼组,差异有统计学意义[44.44%（4／9）比14.29%（1／7）,P＝0.017]。治疗3个周期,氟马替尼600 mg／d 组 bcr-ablIS≤10%的患者比例高于伊马替尼组,差异有统计学意义（P＝0.002）;药代动力学／药效动力学分析也提示氟马替尼600 mg／d 较400 mg／d 更有可能使患者在早期获得分子学反应。在安全性方面,氟马替尼400 mg／d 组、氟马替尼600 mg／d 组和伊马替尼组Ⅲ～Ⅳ级不良事件的发生率差异无统计学意义（P＞0.05）。氟马替尼组较常见皮肤毒性和胃肠道反应,常见的不良事件为腹泻,未发生心脏和心血管系统不良反应,水肿的发生率低于伊马替尼组。结论氟马替尼可以安全有效地治疗初诊 Ph+ CML-CP 患者,600 mg／d 是一个较为合适的临床起始剂量。氟马替尼和伊马替尼在临床上具有相似的安全性。     

安罗替尼联合替吉奥治疗三线及以上晚期非小细胞肺癌的安全性和有效性

目的:前瞻性应用安罗替尼联合替吉奥治疗三线及以上晚期非小细胞肺癌，观察临床疗效和药物的安全性。方法:均经组织病理或细胞学明确诊断晚期非小细胞肺癌，且二线化疗治疗后疾病进展。口服安罗替尼胶囊8 mg/d，d1~14联合替吉奥胶囊60 mg/m2 bid d1~14，21天为一个周期。治疗终止时间为疾病进展或出现不可接受的毒副反应。结果:本研究结果显示，总体客观缓解率（ORR）可达到26.8%，总体疾病控制率（DCR）可达到80.5%，中位无进展生存期（mPFS）达到5.2个月（95%CI:3.9~6.6个月）。单因素分析，脑转移组患者mPFS（4.8个月）对比无脑转移组患者mPFS（5.9个月），两组差异具有统计学意义（P=0.039）。多变量回归分析显示，ECOG评分(P=0.002)、治疗线数（P=0.015）和疗效(P=0.014)是PFS的独立影响因素。最常见毒副反应为高血压、蛋白尿、骨髓抑制、胃肠道反应、疲乏和口腔黏膜炎。结论:安罗替尼联合替吉奥胶囊在晚期非小细胞肺癌三线及以上治疗中，其总体的疗效确切且药物毒副反应可控。     

阿帕替尼治疗难治性鼻咽癌的疗效和生存分析

  目的  评价阿帕替尼治疗难治性鼻咽癌的疗效及安全性并探索预后不良因素。  方法  回顾性分析2016年9月至2019年4月郑州大学第一附属医院接受阿帕替尼治疗66例难治性鼻咽癌患者资料,采用Kaplan-Meier法及Cox模型分析疗效及影响生存的相关因素。  结果  阿帕替尼治疗难治性鼻咽癌的客观缓解率为33.33%,疾病控制率为54.55%。中位无进展生存时间（progres?sion-free survival time,PFS）为7个月（95%CI:2.816~11.184）,中位总生存时间（overall survival,OS）为20个月（95%CI:11.496~28.504）。评价66例患者不良反应,最常见的不良反应为蛋白尿40.90%（27/66）、高血压45.45%（30/66）、手足综合征37.88%（25/66）,无4级不良反应发生;Cox单因素分析显示乳酸脱氢酶水平是PFS的影响因素,WHO病理类型是OS的影响因素。  结论  难治性鼻咽癌应用阿帕替尼治疗可能具有一定疗效,不良反应可控制,对于依从性好、无其他有效治疗方案的难治性鼻咽癌患者可考虑选择,但仍需大样本前瞻性研究证实。      

阿帕替尼相关手足皮肤反应表现和治疗研究进展

甲磺酸阿帕替尼片为一种新型小分子单克隆抗体，作用机制是高度选择性竞争细胞内血管内皮生长因子受体-2（vascularendothelial growth factor receptor-2，VEGFR-2）的ATP结合位点，阻断下游信号转导，抑制肿瘤组织新血管生成。手足皮肤反应（hand-foot skin reaction，HFSR）为阿帕替尼常见的不良反应之一，影响患者的生存质量，导致靶向药减量，从而影响抗肿瘤治疗的疗效。常规的西医治疗为尿素和糖皮质激素外用制剂，临床常根据红肿、破溃、结痂等不同皮肤表现的进行中西医结合治疗。本文对阿帕替尼相关HFSR的表现及治疗进展予以综述，以期给临床提供参考。      

阿帕替尼对人胆管癌细胞增殖和凋亡的影响

目的研究阿帕替尼对体内外胆管癌(CCA)细胞增殖和凋亡的影响,并阐明其作用机制。方法对培养的人CCA细胞系HCCC9810和HCCCT1进行细胞增殖和集落形成能力评价;应用AnnexinV/PI染色法和流式细胞术检测凋亡;在裸鼠移植瘤模型上评估阿帕替尼的体内抗肿瘤作用。结果阿帕替尼对CCA细胞具有剂量依赖性的抗肿瘤作用,其作用机制是抑制细胞增殖和诱导细胞凋亡。另外,阿帕替尼也能抑制HuCCT1裸鼠移植瘤的生长。结论阿帕替尼能抑制体内外CCA细胞增殖并诱导其细胞凋亡。     

Polymorphisms in GSTM1, GSTT1 and CYP1A1 and risk of pancreatic adenocarcinoma

A prospective study of 149 unselected incident cases of pancreatic adenocarcinoma and 146 ethnically-matched controls found no associations between GSTM1 (adjusted odds ratio (AOR) 1.14), GSTT1 (AOR: 1.19) and CYP1A1 (AOR: 1.08) polymorphisms and pancreatic cancer susceptibility. Smoking and drinking status did not affect results. These polymorphisms do not appear to be important gene modifiers in pancreatic cancer.     

Genetic polymorphisms of SULT1A1 and SULT1E1 and the risk and survival of breast cancer.

We examined whether common single nucleotide polymorphisms (SNP) in SULT1A1 (c.779G>A, *14A>G, and *85C>T) and SULT1E1 (IVS1-447C>A, IVS4-1653T>C, and *959G>A) genes influenced the risk and survival of breast cancer. Our study population consisted of 989 histologically confirmed sporadic breast cancer patients and 1,054 controls without history of cancer recruited from three teaching hospitals in Seoul. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression model. In the survival analysis for 529 breast cancer patients with completed treatments, the hazard ratios (HR) were calculated with Cox proportional hazard model. Women with the SULT1E1 *959 GA/AA genotype had a moderately decreased breast cancer risk compared with those with the GG genotypes (OR, 0.8; 95% CI, 0.70-1.00). When the haplotypes were considered, the homozygous *959 AA genotype together with the IVS4-1653 T>C base change (CTA-CCA haplotype) was associated with halved breast cancer risk (OR, 0.5; 95% CI, 0.24-0.88) compared with the wild type CTG-CTG haplotype. No other significant overall association was observed between the SULT1A1 and SULT1E1 SNPs nor haplotypes and breast cancer risk. When stratified by survival, patients with the SULT1E1 IVS4-1653 TC/CC genotypes showed a >3-fold risk of recurrence (HR, 3.2; 95% CI, 1.39-7.48) compared with those with the TT genotype. Moreover, when the haplotypes were considered, the SULT1E1 *959 G>A base change together with the IVS4-1653 T>C base change (CTG-CCA haplotype) was associated with a >4-fold risk of breast cancer (OR, 4.2; 95% CI, 1.15-15.15). These findings suggest that genetic polymorphisms of SULT1E1 are associated with increased risk and a disease free survival of breast cancer in Korean women.     

谷胱苷肽S转硫酶T1、M1和P1基因多态性与结直肠癌易感性的关系

目的研究谷胱苷肽S转硫酶T1、M1和P1(GSTT1、GSTM1和GSTP1)多态性与结直肠癌易感性的关系。方法在江苏省进行了1个病例—对照研究(结直肠癌患者315例,人群对照439例),调查研究对象的生活习惯,抽取静脉血,提取白细胞DNA,以多重PCR技术检测GSTT1和GSTM1基因缺失,PCR-RFLP技术检测GSTP1基因单核苷酸多态(第104密码子A→G)。结果①在结直肠癌组和正常组GSTT1和GSTM1基因缺失频率分别为55.24%、57.31%和72.70%、73.29%、差异无显著性。②在结直肠癌组GSTP1 A/A、A/G和G/G基因型分布频度分别为57.51%、36.74%和5.75%;对照组分别为63.70%、31.05%和5.25%,2组之间差异无显著性(χ2 MH=2.993,P=0.224)。与GSTP1 A/A基因型携带者相比,G/G基因型者发生结直肠癌的危险性无显著升高,其性别、年龄、吸烟、饮酒习惯调整后的OR为1.09(95%CI:0.79~1.51)。结论GSTT1、GSTM1基因缺失型和GSTP1 G/G基因型与结直肠癌的易感性无显著相关。     

Meta- and pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer.

Sequence variation in the GSTM1, GSTT1, GSTP1, and CYP1A1 genes may potentially alter susceptibility to head and neck cancers, although evidence from previous studies has not been consistent. To explore these associations, we conducted a meta-analysis of 31 published case-control studies (4635 cases and 5770 controls) and a pooled analysis of original data from nine published and two unpublished case-control studies (2334 cases and 2766 controls). In the meta-analysis, the summary odds ratios (ORs) for head and neck cancer were 1.23 [95% confidence interval (95% CI), 1.06-1.42] for the GSTM1 null genotype, 1.17 (95% CI, 0.98-1.40) for the GSTT1 null genotype, 1.10 (95% CI, 0.92-1.31) for carrying the GSTP1 Val105 allele, and 1.35 (95% CI, 0.95-1.82) for carrying the CYP1A1 Val462 allele. The pooled analysis ORs were 1.32 (95% CI, 1.07-1.62) for the GSTM1 null genotype, 1.25 (95% CI, 1.00-1.57) for the GSTT1 null genotype, 1.15 (95% CI, 0.86-1.53) for carrying the GSTP1 Val105 allele, and 0.98 (95% CI, 0.75-1.29) for carrying the CYP1A1 Val462 allele. Increasing risk of head and neck cancer was observed with inheritance of increasing numbers of modest risk genotypes at the three GST loci (P for trend = 0.04), with the combination of carrying the GSTM1 null, GSTT1 null, and GSTP1 Val105 alleles conferring an OR of 2.06 (95% CI, 1.11-3.81). In conclusion, both the meta- and pooled analysis support modest associations of GSTM1 and GSTT1 genotypes with head and neck cancer risk, and our pooled analysis supports the notion of greater risk when genotypes at multiple GST loci are considered in a multigenic model.     

Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk

Genetic polymorphisms of the genes encoding for the xenobiotic metabolizing enzymes result in individual variations in the efficiency of detoxification of environmental carcinogens, and have been extensively associated with variable risk for lung neoplasms in different ethnic and environmental backgrounds. In this study, using PCR-RFLP based assays, we investigated the distribution of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in Greek lung cancer patients (N=122) and healthy controls (N=178). The frequency of CYP1A1 m1 homozygous genotype was 0.04 in patients and 0.02 in controls (detected in 4.10% of patients and in 1.69% of controls, respectively), that of GSTM1 null genotype was 0.52 in patients and 0.54 in controls, whereas those of GSTT1 null genotype was 0.17 and 0.11, in patients and controls, respectively. The GSTM1 null genotype was more frequent in adenocarcinoma, as well as in lung cancer patients with history of chronic obstructive pulmonary disease (COPD). The GSTT1 null genotype correlated with advanced age of the patients at the time of diagnosis. Three combinations of rare genotypes - in subjects carrying simultaneously deviations from the common genotype in more than one gene - were over-represented in lung cancer patients, compared to control population, and were furthermore significantly associated with history of heavy tobacco consumption in lung cancer patients. The results imply involvement of specific genotype combinations of CYP1A1, GSTM1 and GSTT1 alleles in the development of lung cancer in heavy smokers.     

Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations

This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases micro1 (GSTM1) and 1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.     

CYP1A1和NQO1及EPHX1基因多态性与膀胱癌易感相关性分析

目的:探讨细胞色素P450 1A1(CYP1A1)、依赖还原型辅酶Ⅰ/Ⅱ醌氧化还原酶1(NQO1)和环氧化物水解酶(EPHX1)基因多态性与浙江地区膀胱癌易感性的关系.方法:采用病例对照研究方法,应用相对的2对引物-聚合酶链反应技术(PCR-CTPP),对99例膀胱癌患者和100例非肿瘤患者的CYP1A1 A4889G、NQO1 C609T和EPHX1 A416G基因型进行检测,并分析其与膀胱癌易感性的关系.结果:NQO1 C609T基因型分布频率在膀胱癌组和对照组之间的差异有统计学意义,P＜0.05;携带609TT基因型的个体罹患膀胱癌的风险是携带609CC基因型个体的2.448倍(95％CI为1.125～5.326).CYP1A1 A4889G和EPHX1 A416G基因型分布频率在两组间的差异均无统计学意义,P＞0.05.携带NQO1 609TT与EPHX1 416AA两高危基因型的个体罹患膀胱癌的风险是同时携带两低危基因型个体的4.181倍(95％CI为1.465～11.934).相类似的,携带CYP1A1 4889AG/GG、NQO1 609TT与EPHX1 416AA三高危基因型的个体罹患膀胱癌的风险则为4.765倍(95％CI为0.895～25.364).结论:NQO1 C609T基因多态性可能与膀胱癌的易感性相关,携带NQO1 609TT基因型的人群易患膀胱癌.而且,基因与基因(NQO1 609TT与EPHX1 416AA,CYP1A1 4889AG/GG、NQO1 609TT与EPHX1 416AA)的交互作用增加了这种风险.