Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors.

BACKGROUND: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. PATIENTS AND METHODS: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). RESULTS: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C(max) was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days). CONCLUSIONS: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.     

抗瘤增效方联合吉非替尼治疗老年非小细胞肺癌患者及对炎症因子,T细胞亚群水平及血清肿瘤标志物的影响

目的:探讨抗瘤增效方联合吉非替尼治疗老年非小细胞肺癌及对患者炎症因子,T细胞亚群水平及血清肿瘤标志物影响。方法:选取郑州大学附属肿瘤医院肿瘤内科非小细胞肺癌Ⅳ期老年患者84例,患者或家属签字同意,积极配合此次研究,按随机数字表法分组,对照组患者(42例)予以单纯吉非替尼治疗,研究组患者(42例)予以吉非替尼联合抗瘤增效方治疗,观察并记录所有患者治疗前后生存质量、炎症因子及T细胞亚群水平,同时对比临床疗效及不良反应状况。结果:对照组有效率低于研究组(P0.05);与治疗前比较,两组患者治疗后生存质量、炎症因子及T细胞亚群水平均发生变化,研究组治疗后躯体功能,角色功能,社会功能,情绪功能评分高于对照组,研究组治疗后白细胞介素-2(interleukin-2,IL-2),白细胞介素-12(interleukin-12,IL-12)和γ-干扰素(interferon-γ,IFN-γ)水平高于对照组,研究组治疗后CD8+水平低于对照组,CD4+及CD4+/CD8+水平高于对照组(P0.05);治疗后,对照组血管内皮生长因子(vascular endothelial growth factor,VEGF)升高,治疗组VEGF下降(P0.05);与治疗前比较,两组患者癌胚抗原(carcinoembryonic antigen,CEA),糖抗原(carbohydrate antigen-125,CA125)及细胞角蛋白19片段21-1(cytokeratin 19 fragments,CYFRA21-1)差异无统计学意义,组间比较差异无统计学意义;两组患者不良反应较轻,无药物不良反应。结论:抗瘤增效方联合吉非替尼治疗老年非小细胞肺癌疗效确切,能提高生活质量及免疫功能。     

吉非替尼对肺鳞癌患者免疫功能的影响及其近期临床疗效

目的：研究吉非替尼对肺鳞癌患者免疫功能的影响及其近期临床疗效。方法选取诊断为肺鳞癌的患者84例,随机分为观察组和对照组,每组均为42例,两组患者均给予常规治疗,观察组在常规治疗的基础上给予口服吉非替尼,观察两组患者治疗后体液免疫和细胞免疫功能情况及其近期临床疗效。结果治疗后两组患者血清 CD3、CD4、IgG、IgM、IgA 浓度与 CD4／CD8较治疗前有所降低（P ＜0．05）,CD8较治疗前有所升高（P ＜0．05）;观察组患者血清 CD3、CD4、CD4／CD8、IgG、IgM、IgA 浓度明显高于对照组（P ＜0．05）,观察组 CD8较对照组低（P ＜0．05）;观察组临床疗效优于对照组,治疗后两组均出现恶心、恶心伴呕吐、骨髓抑制,差异无统计学意义（P ＞0．05）。结论在常规治疗的基础上给予口服吉非替尼能改善患者的免疫功能,提高临床疗效,且无严重不良反应。     

吉非替尼对A549细胞增殖及细胞周期、凋亡的作用

目的：观察吉非替尼对人非小细胞肺癌A549的生长增殖、细胞周期及细胞凋亡的影响。方法：用5—40μmol／L浓度范围内的吉非替尼和A549细胞共培养24、48、72h,采用四甲基偶氮唑蓝（MTr）法检测吉非替尼对细胞增殖的影响;用流式细胞仪检测其对细胞凋亡及细胞周期分布的影响;利用抗Capspase-3的ELISA（酶联免疫吸附）法检测是否发生细胞凋亡。结果：在5—40μmol／L浓度范围内,吉非替尼对A549细胞的增殖有明显的抑制作用,并呈时间和剂量依赖性,以40μmol／L作用72h时的抑制率最高。流式细胞仪检测显示10μmol／L-401μmol／L的吉非替尼作用可使细胞发生G0／G,期阻滞,但即使作用48h也未发现凋亡细胞。ELISA法显示48h内,吉非替尼组与正常细胞组的Capspase-3浓度无统计学差异,但作用72h时出现凋亡。结论：吉非替尼在5—40μmol／L浓度下作用时间小于48h时,其对A549细胞的增殖抑制可能是通过阻滞A549细胞于G0／G1期而非引起细胞凋亡实现的,但作用时间达到72h时,其可以诱导A549发生细胞凋亡。     

早期非小细胞肺癌体部立体定向放疗基础和临床研究——不同照射剂量联合吉非替尼对肺癌细胞系H358的影响

目的：探讨不同剂量单纯照射及照射联合吉非替尼对非小细胞肺癌细胞系 H358存活率、增敏比及细胞凋亡、细胞周期的影响。方法体外培养肺腺癌细胞 H358分为空白对照组、单纯照射组、单纯吉非替尼（Iressa）组、照射＋Iressa组,照射剂量为0、2、4、6、8、12、16、20 Gy,药物浓度为1μmol/L。通过细胞克隆形成实验,观察4组 H358细胞存活情况,描绘细胞存活曲线;采用四噻唑比色试验（MTT）观察两组细胞生长受抑制情况,计算增敏比（SER）;运用流式细胞仪检测细胞凋亡率和细胞周期。结果（1）随着照射剂量增加细胞存活分数减小,单纯照射组单次剂量达到20 Gy时,细胞克隆集落形成率为0,照射＋Iressa组单次剂量达到16 Gy时克隆集落形成率为0;（2）照射＋Iressa 组与单纯照射组相比,两组 OD 值差异有统计学意义（F剂量＝62．644,P ＜0．001,F药物＝233．572,P ＜0．001）,两组 OD值随着照射剂量的增高而减小,不同剂量之间 OD值差异有统计学意义（F未加药＝354．972,P＜0．001;F加药＝231．740,P ＜0．001）,两组细胞放射增敏比（SER）与药物显著相关（P ＜0．001）,照射＋Iressa组SER较单纯照射组明显增高;（3）随着照射剂量的增加,凋亡率增高（P ＜0．001）,H358细胞凋亡率与Iressa药物作用相关（P ＜0．001）,单纯Iressa作用后细胞周期阻滞主要出现在G0/G1期,照射＋Iressa组及单纯照射组主要出现G2/M期阻滞。结论增加单次照射剂量可降低 H358细胞存活率,细胞凋亡与 Iressa药物之间存在相关性,照射＋Iressa能够增加细胞凋亡率,照射前使用Iressa能够增强照射对细胞的放射敏感性。     

EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small-cell lung cancer

The incidence of brain metastasis (BM) is high in patients with non-small-cell lung cancer. Available standard therapeutic options, such as whole-brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. Novel agents, such as EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs), have now been included in standard non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by a response rate of 70–80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. However, since most of the larger studies on these agents have excluded BM patients from their series, few prospective data are available on the efficacy of these agents in this setting. In recent years, however, several authors have reported a growing number of cases of partial and complete response in BM patients treated with EGFR TKIs. Data from retrospective series and Phase II studies also suggest that a response can be obtained using EGFR TKI treatment for patients with BM, especially those harboring EGFR mutations.     

A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer

Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naïve patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naïve patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m² d1) and either cisplatin (75 mg/m² d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed–platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations.     

Personalized medicine for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is a heterogeneous illness associated with a high mortality rate. Personalized therapy may improve treatment outcomes by identification of a specific genotypic anomaly and target-specific therapy. The most significant development in recent years was the discovery of activated EGF receptor (EGFR) mutations at exons 19 and 21. Patients with EGFR mutations respond dramatically to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib, resulting in longer progression-free survival. Multiple randomized studies, including the Iressa Pan-Asia Study and WJTOG3405, have confirmed the role of EGFR tyrosine kinase inhibitors as standard first-line therapy for patients with the EGFR mutation. In this article, we summarize the current nonpersonalized therapies and examine the available and investigational personalized therapies for patients with resectable early-stage, unresectable locally advanced, or metastatic disease.     

金复康口服液对吉非替尼耐药人肺腺癌PC9/R的增敏作用和机制研究

目的 研究金复康口服液对人肺腺癌PC9细胞及耐药PC9/R细胞的吉非替尼增敏作用及机制。方法 金复康口服液20 mg/mL联合不同浓度的吉非替尼（40、20、10、5、2 μmol/L）作用于PC9/R细胞,CCK-8法检测细胞增殖;培养PC9、PC9/R细胞,分为对照组、金复康口服液组、吉非替尼组、联合用药组,流式细胞术检测PC9、PC9/R细胞周期和凋亡。在BALB/c裸鼠右前肢腋窝皮下接种PC9/R细胞建立裸鼠移植瘤模型,观察金复康口服液联合吉非替尼的体内抑瘤作用;对AKT、p-AKT、PTEN、PDCD4蛋白表达的影响和对miRNA-21表达的影响。结果 与吉非替尼（2、5、10、20 μmol/L）组比较,吉非替尼（2、5、10、20 μmol/L）+金复康口服液（20 mg/mL）组的PC9/R细胞抑制率显著增加（P<0.01）;与吉非替尼组比较,联合用药可以通过显著增加早期凋亡细胞比例诱导PC9及PC9/R细胞凋亡,并使PC9、PC9/R细胞停滞在DNA合成前期,从而抑制细胞增殖,差异均具有统计学意义。体内实验表明,与吉非替尼组比较,联合用药显著抑制裸鼠PC9/R移植瘤的生长（P<0.05）,且能显著降低裸鼠PC9/R组织p-AKT表达（P<0.05）,增强PTEN、PDCD4的表达（P<0.05）,联合用药组裸鼠PC9/R瘤组织miRNA-21的表达显著降低（P<0.05）。结论 金复康口服液能提高人肺腺癌PC9/R细胞对吉非替尼的敏感性,其作用的可能机制为通过降低miRNA-21的表达从而增强PTEN、PDCD4的表达以抑制AKT通路活性。