吉非替尼联合培美曲塞治疗吉非替尼二线治疗进展后肺腺癌的疗效观察

目的观察吉非替尼联合培美曲塞治疗吉非替尼二线治疗进展后肺腺癌的疗效及安全性。方法选取2010年10月至2012年12月间74例一线化疗进展后给予吉非替尼治疗有效再次进展患者,随机分为观察组和对照组两组。观察组患者36例,采用培美曲塞500mg/m2,静脉滴注;吉非替尼250mg/d,口服,21d为1个周期;对照组患者38例,单用培美曲塞500mg/m2,静脉滴注,21d为1个周期。所有患者至少治疗2个周期。结果观察组近期治疗效果优于对照组,但两组差异无统计学意义;与对照组相比,观察组死亡率略低,中位进展时间和中位生存时间均更长,两组在死亡率、生存时间和进展时间方面比较,差异无统计学意义（P〉0.05）;两组不良反应差异无统计学意义（P〉0.05）。结论采用吉非替尼二线治疗进展后联合培美曲塞治疗非小细胞癌肺腺癌,其治疗效果明显,不良反应能耐受,有利于提高肺腺癌患者的生活质量,有望成为非小细胞肺癌（NSCLC）患者标准的三线治疗方案。     

Mir-7上调增强肺腺癌对吉非替尼敏感性的机制研究

目的:探索上调Mir-7的表达使肺腺癌A549细胞增强吉非替尼的敏感性及其机制。方法:用lipo-fectamine2000携带Mir-7对A549细胞进行瞬时转染。将A549细胞分为对照组、转染组、吉非替尼组与联合组。MTT法测各组细胞增殖率变化,Transwell检测细胞侵袭性,Real time PCR检测E-Cadherin及N-Cad-herin的mRNA表达的变化,Western blot检测他们的蛋白表达的变化。结果:上调A549细胞中Mir-7的表达与吉非替尼共同作用较单独吉非替尼作用有更显著的抑制作用。用Mir-7转染后,肺腺癌A549细胞的侵袭力下降。转染与吉非替尼联合组E-Cadherin的信使RNA及蛋白的表达变化不大,但N-Cadherin表达下降。结论:上调Mir-7的表达可以增强肺腺癌细胞对吉非替尼的敏感性,其机制可能是过量表达的Mir-7抑制了IGF-1R信号通路及肿瘤上皮细胞间质化。     

对256例服用吉非替尼非小细胞肺癌患者的药学监护体会

目的 探讨对256例服用吉非替尼非小细胞肺癌患者实施药学监护的过程、方法 及其作用。方法 选取2017年10月至2019年10月在我院肿瘤科住院的服用吉非替尼的非小细胞肺癌患者256例,对照组给予常规药物治疗,观察组在药物治疗基础上给予针对性药学监护措施,对其不良反应相应给予不同的应对方案,整理、归纳和分析两组的治疗总有效率、不良反应总发生率和因不良反应导致的总停药率。结果 观察组的治疗总有效率为48.44%,明显高于对照组的28.12%,差异有统计学意义(P0.05);两组不良反应总发生率比较,差异无统计学意义(P0.05);观察组因不良反应导致的总停药率为25.78%,明显低于对照组的40.63%,差异有统计学意义(P0.05)。结论 通过对吉非替尼不良反应的针对性药学监护,使其疗效显著升高、停药率显著降低,大大提高了患者的依从性。     

Antitumor effect of Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with cytotoxic agent on murine hepatocellular carcinoma

AIM: To investigate the inhibitory effect of gefitinib combined with cytotoxic agent cisplatin (CDDP) on hepatocellular carcinoma (HCC). METHODS: Female Kunming mice and H22 hepatocarcinoma cells were used. Gefitinib at daily dose of 100 mg/kg body weight (BW) or lecithin liquid was given by gastrogavage once a day for 5 or 10 successive days. CDDP or normal saline (NS) was administered intraperitoneally (i.p.) once a day for 5 successive days. Mice were randomly divided into control group (lecithin, or NS, i.p.), CDDP group (daily dose, 1.2 mg/kg BW; d1-5, or d6-10), Gefitinib (d1-5, or d6-10, or d1-10), and Gefitinib combined with CDDP groups. The inhibitory rate (IR) of tumor, net BW, spleen index (SI), thymus index (TI) and the amount of peripheral blood cells of mice were detected on the 12th experiment day. RESULTS: The growth of HCC in mice was inhibited by Gefitinib alone (IR: 41% in d1-10 group and 30% in d1-5 group, respectively) or CDDP alone (IR: 32-54% in d1-5 group or d6-10 group). The highest inhibitory effect (IR: 56%) on HCC growth was observed in Gefitinib (d1-10) combined with CDDP (d1-5) group. Higher inhibition was also observed in CDDP (d1-5) followed by Gefitinib (d6-10) group than that in Gefitinib (d1-5) followed by CDDP (d6-10) group (IR: 61% vs 36%, P<0.01) in the independent study. Net BW, SI, TI and the amount of blood cells of mice in Gefitinib alone group were not significantly different from those in control groups. CONCLUSION: Gefitinib can significantly inhibit the growth of murine H22 hepatocellular carcinoma. If Gefitinib is used after CDDP treatment in animal experiments, the inhibitory effect could be enhanced.     

Post-Progression Survival in Patients with Non-Small Cell Lung Cancer with Clinically Acquired Resistance to Gefitinib

Most patients with tyrosine kinase inhibitor (TKI)-sensitive non-small cell lung cancer (NSCLC) eventually develop acquired resistance to TKIs. Factors that affect TKI-sensitive patient survival after progression during TKI treatment remain unknown. We attempted to identify factors that affected post-progression survival. We retrospectively reviewed 81 advanced NSCLC patients with disease progression following tumor response and durable (≥ 6 months) disease stabilization with first-line or second-line gefitinib. Post-progression survival (PPS) and characteristics were investigated and compared in patients who did (n = 16) and did not (n = 65) resume TKIs. Most patients were female never-smokers with adenocarcinoma. Median overall PPS was 10.3 months (95% confidence interval [CI], 7.458-13.142). Age, gender, smoking history, histology, Eastern Cooperative Oncology Group performance status at gefitinib initiation, initial stage, and platinum-based chemotherapy after gefitinib were not significant predictors of PPS. Pemetrexed use after gefitinib significantly improved PPS (18.5 vs 8.6 months; hazard ratio [HR], 0.45; P = 0.008). Gefitinib reuse tended to lengthen PPS but was insignificant in multivariate analysis (27.4 vs 8.8 months; HR, 0.53; P = 0.095). NSCLC patients assumed to have clinically acquired resistance to TKIs had relatively long PPS. TKIs reuse or pemetrexed use after progression with gefitinib may improve PPS.     

肺金生方抗非小细胞肺癌EGFR-TKIs耐药性的分子机制研究

目的探讨肺金生方抗非小细胞肺癌(NSCLC)酪氨酸磷酸酶抑制剂(TKIs)靶向药物耐药的作用及分子机制。方法选用NSCLC细胞系HCC827,按0.01、0.05、0.10、0.50和1.0μM浓度梯度诱导构建吉非替尼耐药细胞株,采用CCK8法检测耐药株是否构建成功,采用荧光定量PCR(q-PCR)检测耐药株c-MET扩增水平。20只BALB/c裸鼠按随机数字表法分成空白对照组、吉非替尼组、肺金生方组和肺金生方+吉非替尼组,每组5只。按每只4×10~7/200μL将吉非替尼耐药细胞株注射于裸鼠后肢皮下,构建皮下移植瘤模型。四组均腹腔注射生理盐水,吉非替尼组给予吉非替尼50mg/kg灌胃;肺金生方组给予肺金生方剂量53.6g/kg灌胃;肺金生方+吉非替尼组给予吉非替尼50mg/kg+肺金生方剂量53.6g/kg联合灌胃给药。给药频次每2天1次,连续给药4周。CCK8法检测耐药HCC827 GR细胞增殖率,流式细胞技术检测耐药HCC827 GR细胞凋亡率,Western blot检测耐药HCC827 GR细胞p-EGFR、p-MET、p-AKT、p-ERK1/2表达水平。结果与空白对照组比较,吉非替尼组裸鼠皮下移植瘤瘤重无差异[(1.34±0.16)g比(1.41±0.13)g,P>0.05],肺金生方组裸鼠皮下移植瘤瘤重明显减轻[(0.77±0.28)g比(1.41±0.13)g,P<0.01],吉非替尼+肺金生方组裸鼠皮下移植瘤明显小于肺金生方组和吉非替尼组[(0.34±0.16)g比(0.77±0.28)g、(1.34±0.16)g,P均<0.01];肺金生方单用或与吉非替尼联用能够明显抑制耐药HCC827 GR细胞的增殖能力[(43.45±4.47)%、(24.25±5.21)%比(100.00±2.14)%,P均<0.01];肺金生方组、吉非替尼+肺金生方组细胞凋亡率显著高于空白对照组[(7.40±0.56)%、(12.80±0.72)%比(3.05±0.54)%,P均<0.01];肺金生方组、吉非替尼+肺金生方组c-MET和p-c-MET表达水平明显降低,并明显抑制下游AKT/ERK1/2磷酸化水平。结论肺金生方或和吉非替尼联用能有效抑制吉非替尼耐药皮下移植瘤的生长,抑制耐药细胞的增殖并促进凋亡,其作用机制可能与下调c-MET蛋白表达以及下游AKT/ERK1/2磷酸化水平有关。     

Are erlotinib and gefitinib interchangeable,opposite or complementary for non-small cell lung cancer treatment? Biological,pharmacological and clinical aspects

Gefitinib and erlotinib are the two anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) approved for treatment of advanced NSCLC patients. These drugs target one of the most important pathways in lung carcinogenesis and are able to exploit the phenomenon of ‘oncogene addiction’, with different efficacy according to EGFR gene mutational status in tumor samples. Gefitinib has been approved only for EGFR mutation bearing patients regardless the line of treatment, while erlotinib is also indicated in patients without EGFR mutation who undergo second- or third-line treatment. Some studies evaluated the main differences between these drugs both for direct comparison and to improve their sequential use. In particular, toxicity profile resulted partially different, and these observations may be explained by several molecular and pharmacokinetic features. Therefore, this review integrates preclinical data with clinical evidences of TKIs to guide the optimization of currently available treatments in advanced NSCLC patients.     

表皮生长因子受体抑制剂在非小细胞肺癌治疗中的研究进展

化疗一直是晚期非小细胞肺癌(NSCLC)的主要治疗手段之一,但是治疗的有效率仅为30％左右,且具有较大的不良反应,耐药和血液学的不良反应是患者预后不良的主要原因之一.随着分子生物标记如表皮生长因子受体(EGFR)等的发现和相应靶向药物的研发与批准应用,肺癌的治疗正在发生重大变化.大量研究证实EGFR抑制剂靶向治疗能改善NSCLC患者的疾病无进展期和生活质量,而正确的选择合适的患者是靶向治疗成功的关键.本文将对EGFR的组成及活化、检测方法、EGFR靶向药物在NSCLC治疗中的作用以及获得性耐药患者的治疗进展进行综述.