Interactions of crizotinib and gefitinib with organic anion-transporting polypeptides (OATP)1B1, OATP1B3 and OATP2B1: gefitinib shows contradictory interaction with OATP1B3

1.?The drug–drug interaction (DDI) mediated by organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and OATP2B1 has a major impact on the hepatic clearance of drugs. The effects of tyrosine kinase inhibitors (TKIs) on OATPs have not been well studied. In the present study, we evaluated the contribution of OATPs to the hepatic uptake of crizotinib and gefitinib and the interaction of those TKIs with OATPs to estimate DDIs.

2.?To clarify whether crizotinib and gefitinib were substrates for OATPs, we performed uptake studies. We examined the effects of the TKIs on uptake of typical substrates and fluvastatin via OATPs. IC₅₀ and EC₅₀ values of the TKIs were calculated.

3.?OATP1B3- and OATP2B1-mediated crizotinib uptake and OATP2B1-mediated gefitinib uptake were observed. Gefitinib accelerated OATP1B3-mediated [³H]TCA uptake and inhibited OATP2B1-mediated [³H]E₃S uptake. On the other hand, gefitinib inhibited OATP1B1- and OATP2B1-mediated fluvastatin uptake.

4.?We provided basic information to estimate the DDI on OATPs caused by TKIs. The DDI on OATPs caused by gefitinib could occur in a normal clinical situation. And the uptake of crizotinib into the intrahepatocellular environment via OATPs may induce DDI and liver damage. We therefore emphasize the necessity of careful use of TKIs.     

吉非替尼通过调控hPTTG1表达抑制卵巢癌细胞增殖并诱导凋亡的机制研究

目的：吉非替尼和人垂体瘤转化基因1（hPTTG1）对卵巢癌细胞增殖和凋亡的影响及作用机制。方法：以不同浓度吉非替尼干预A2780细胞,MTT法检测细胞增殖。流式细胞仪、qRT-PCR和Western blot实验检测20 μmol·L^-1吉非替尼对A2780细胞凋亡及细胞中hPTTG1表达的影响。敲减hPTTG1或过表达hPTTG1联合20 μmol·L^-1吉非替尼处理,qRT-PCR和Western blot、MTT和流式细胞术检测细胞中hPTTG1表达及细胞增殖、凋亡情况变化。结果：吉非替尼能够有效抑制A2780细胞增殖（P<0.05）,呈浓度依赖性。以20 μmol·L^-1吉非替尼干预A2780细胞,细胞凋亡率升高（P<0.05）,细胞中hPTTG1在mRNA和蛋白水平的表达显著下调（P<0.05）。将hPTTG1 siRNA转染至A2780细胞后,细胞hPTTG1表达水平降低（P<0.05）,细胞增殖抑制率和凋亡率增大（P<0.05）;过表达hPTTG1可减弱吉非替尼对A2780细胞增殖的抑制及凋亡的促进作用。结论：吉非替尼可抑制A2780细胞增殖并诱导凋亡,这一结果可能是通过抑制hPTTG1表达来完成。     

肿瘤靶向药物与中医药方剂联合治疗非小细胞肺癌患者的临床研究

目的：探讨肿瘤靶向药吉非替尼与中医药方剂益气除痰方联合治疗非小细胞肺癌（NSCLC）的临床疗效研究。方法：将80例非小细胞肺癌患者随机分为2组,每组各40例,治疗组用中医药益气除痰方联合吉非替尼治疗,对照组单用吉非替尼药物治疗。观察治疗前后2组NSCLC患者瘤体大小,血清肿瘤标志物（CEA、SCC）,T淋巴细胞亚群参数,生存质量卡氏评分,不良反应发生率情况,血液生化等指标。结果：肿瘤体大小直径治疗前后比较,治疗组总稳定率高于对照组差异具有显著性（P<0.05）;肿瘤标志物治疗前后比较,2组均能降低,但治疗组总体上优于对照组,差异具有显著性（P<0.05）;T淋巴细胞亚群（CD3⁺、CD4⁺、CD8⁺）治疗前后比较,2组均能提高参数,但治疗组总体上优于对照组,差异具有显著性（P<0.05）;生存质量卡氏评分、不良反应发生率治疗前后比较,治疗组明显低于对照组,差异有显著性（P<0.05）。结论：中医药益气除痰方联合吉非替尼治疗NSCLC较单用吉非替尼药物疗效好,并能有效改善患者生存质量,提高患者机体免疫力,减少不良反应发生率。     

A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis

IntroductionClinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib.MethodsThis was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m² intravenously 3-weekly + 250 mg/day orally) or gefitinib.ResultsIn total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event.ConclusionsAddition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.     

MicroRNA-145增强非小细胞肺癌细胞对吉非替尼敏感性及其机制探讨

目的:探讨微小RNA-145（microRNA-145,miR-145）对非小细胞肺癌细胞系吉非替尼耐药的作用及其可能的潜在机制。方法:实时荧光定量PCR（Q-PCR）方法检测正常细胞及非小细胞肺癌细胞中miR-145的表达差异;不同时间5 μmol/L吉非替尼干预肺癌细胞SPC-A-1和A549后,Q-PCR检测miR-145表达变化;miR-145 mimics和miR-145 inhibitors分别转染SPC-A-1和A549肺癌细胞后,CCK8检测细胞活力变化;双荧光素酶报告系统检测miR-145与ADAM19的靶向结合;miR-145 mimics转染SPC-A-1和A549肺癌细胞,Western blot检测ADAM19蛋白表达;Western blot检测5 μmol/L吉非替尼干预后,SPC-A-1和A549肺癌细胞中ADAM19蛋白的表达;miR-145 mimics转染SPC-A-1和A549肺癌细胞,再用5 μmol/L吉非替尼干预,Western blot检测ADAM19蛋白的表达;采用siRNA抑制ADAM19表达,再用5 μmol/L吉非替尼干预,CCK8检测细胞活力;采用BALB/C雌性裸鼠皮下接种肿瘤细胞的方法,观察上述效应。结果:Q-PCR结果显示,与正常肺上皮细胞系BEAS-2B相比较,肺癌细胞SPC-A-1和A549中miR-145表达明显降低;5 μmol/L吉非替尼干预SPC-A-1和A549细胞后,miR-145表达显著上调;转染miR-145 mimics后,CCK8结果显示两种细胞细胞活力下降;双荧光素酶报告系统结果显示,miR-145靶向结合ADAM19基因的3'-UTR区;Western blot结果显示,5 μmol/L吉非替尼诱导SPC-A-1和 A549细胞后,两种细胞中ADAM19蛋白表达均降低;miR-145 mimics转染SPC-A-1和A549细胞,之后给予5 μmol/L吉非替尼治疗,ADAM19蛋白表达下调;siRNA抑制SPC-A-1和A549细胞中ADAM19表达,再给予5 μmol/L吉非替尼治疗,CCK8结果显示,两种细胞的细胞活力显著降低;过表达BALB/C雌性裸鼠的miR-145后,显著抑制皮下肿瘤生长,并且增强吉非替尼的抗肿瘤效果。结论:miR-145显著增强肺癌细胞SPC-A-1和A549对吉非替尼的敏感性,其机制可能是通过靶向结合AMDM19基因的3'-UTR区域,从而抑制其表达。miR-145有可能成为治疗非小细胞肺癌吉非替尼耐药的有效靶点。     

肺癌靶向治疗研究:以文献计量学和可视化分析描述的热点与趋势

目的:通过文献计量学分析方法,阐述并分析肺癌靶向治疗的研究热点与趋势。方法:文章检索了万方数据库、Web of Science、SooPAT(中国专利)数据库近10年来国内外肺癌靶向治疗的相关文献,以文献计量学方法,分析并归类了肺癌靶向治疗的研究热点与时效变迁的趋势。结果:在万方数据库3 744篇肺癌靶向治疗的中文文章中,发现作用于表皮生长因子受体基因突变位点的分子靶向药物-吉非替尼治疗非小细胞肺癌的研究是中国学者近10年的主要研究热点;在近10年Web of Science数据库中检索到的810篇英文文章及参考文献显示,西妥昔单抗、贝伐单抗、纳武单抗、吉非替尼、厄洛替尼和环唑替尼为这10年肺癌治疗领域靶向治疗的热点药物,而多种靶向药物的联合治疗、晚期非小细胞肺癌的靶向治疗效果和肺癌靶向治疗后的脑转移也成为近5年该领域的国际关注热点;中国肺癌靶向治疗领域的254项有权专利的分析显示,申报了专利的主要药物包括酸敏感的吉非替尼-氟硼二吡咯衍生物、顺铂抗肺癌主动靶向隐形类脂质体等。结论:文章采用文献计量学的量化分析技术,呈现出近10年肺癌靶向治疗已成为该领域专业研究者持续关注的热点,而如何选择正确的靶向药物或药物组合方案来解决肺癌治疗中的耐药性问题,同时最大程度地减少患者的不良反应,以延长患者的生存率,应是未来集中研究的方向。     

晚期NSCLC吉非替尼治疗失败后的再次治疗(病例报告及文献复习)

目的:对吉非替尼治疗失败后的晚期NSCLC患者再次使用吉非替尼治疗,分析其疗效及安全性。方法:复习1例吉非替尼治疗失败后的晚期NSCLC患者再次使用吉非替尼治疗及临床资料,结合相关文献探讨其临床特征、治疗及预后。结果:该患者首次使用吉非替尼约8月后耐药,停药5月后再次使用吉非替尼,1月后复查肺部CT提示肺部病灶明显缩小,2个月后再次失效,最终总生存期达21月,使用吉非替尼期间不良反应轻微。结论:曾使用吉非替尼有效的晚期NSCLC患者,再次使用吉非替尼仍有可能延长其生存时间且不良反应轻微。     

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.     

Gefitinib is more effective in never-smokers with non-small-cell lung cancer: experience among Asian patients

We retrospectively analysed the results of patients with advanced non-small-cell lung cancer treated with gefitinib to derive clinical factors predictive of response and a favourable survival outcome. Patients were treated with gefitinib 250 mg per day and re-evaluated 4-8 weeks later with repeat CT scan and every 8 weeks thereafter to assess response and the duration of response. Pathology review by a histopathologist was conducted, in particular to confirm a recently published result of bronchioloalveolar carcinoma histology or its components as predictive of response to gefitinib. Logistic regression and Cox regression analytical methods were applied to determine factors that could predict for response and improved overall survival. A total of 110 patients were treated. The overall response rate was 32% partial responses (PRs). Only never-smoking status was predictive of response in the logistic regression analysis, adjusted OR=6.1, 95% CI=1.7, 21.5. The presence of a PR and good performance status were predictive of a favourable survival outcome from the Cox regression modelling. Responders had an adjusted HR of 3.0, 95% CI=1.5-5.8 compared to nonresponders, while patients with ECOG status 0-1 had an adjusted HR of 0.42, 95% CI=0.25-0.72, compared with patients with ECOG status 2-4. Bronchioloalveolar carcinoma or its components were distinctly absent on pathology review. In conclusions, Never-smoking status is an important clinical predictor of a favourable response to gefitinib.     

A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer

Inhibition of epidermal growth factor receptor (EGFR) signalling contributes to the therapy of colorectal cancer. Gefitinib, an oral EGFR tyrosine kinase inhibitor, shows supra-additive growth inhibition with irinotecan and fluoropyrimidines in xenograft models. We designed a study to determine the tolerability and efficacy of gefitinib in combination with irinotecan, infusional 5-fluorouracil (5-FU) and leucovorin (LV), on a 2-week schedule. Among 13 patients with advanced colorectal cancer, 10 required dose reductions of irinotecan and 5-FU because of dehydration, diarrhoea, and neutropenia, seven of whom required hospitalisation, three with neutropenic fever. One patient achieved partial response and seven had disease stabilisation. The combination of this standard chemotherapy regimen with gefitinib is associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level.