Decreased Biosynthesis of Lung Surfactant Constituent Phosphatidylcholine Due to Inhibition of Choline Transporter by Gefitinib in Lung Alveolar Cells

Purpose We investigated whether gefitinib, an anticancer agent, inhibits phosphatidylcholine (PC) biosynthesis and choline uptake by alveolar epithelial type II cells. Materials and Methods Uptake of choline and PC biosynthesis were examined in vitro, using human alveolar epithelia-derived cell line A549 and rat alveolar type (AT) II cells as models. Results Gefitinib reduced the incorporation of [³H]choline into PC in A549 and rat ATII cells. The uptake of [³H]choline by A549 and rat ATII cells was concentration-dependent, and the Km values were 15.0 and 10–100 μM, respectively. The uptake of [³H]choline by A549 and rat ATII cells was weakly Na⁺-dependent, and inhibited by hemicholinium-3. RT-PCR revealed expression of choline transporter-like protein (CTL)1 and organic cation transporter (OCT)3 mRNAs in both cells. The choline uptake by A549 and rat ATII cells was strongly inhibited by gefitinib with the IC₅₀ value of 6.77 μM and 10.5 μM, respectively. Conclusions Our results demonstrate that gefitinib reduces PC biosynthesis via inhibition of cellular choline uptake by A549 and rat ATII cells, which is mainly mediated by CTL1, resulting in abnormality of lung surfactant that can be one of mechanisms of the interstitial lung disease associated with gefitinib.     

白花蛇舌草乙醇提取物联合吉非替尼对TGF-β1诱导的肺腺癌细胞H358上皮间质化的干预作用

目的 研究白花蛇舌草乙醇提取物(ethanol extract of Hedyotis diffusa,EEHD)联合吉非替尼对TGF-β₁诱导的肺腺癌细胞H358上皮间质化的干预作用。方法 以上皮表型人肺腺癌细胞H358为研究对象,TGF-β₁诱导构建细胞上皮间质化模型,按EEHD、吉非替尼及两药3种不同顺序联合作用分为6组：A组,EEHD作用48 h;B组,吉非替尼作用48 h;A24B24组,先EEHD作用24 h,后吉非替尼作用24 h;B24A24组,先吉非替尼作用24 h,后EEHD作用24 h;AB48组,同时加入吉非替尼和EEHD作用48 h;对照组。CCK-8法测定各组细胞坏死率,Western-blot检测各组细胞中E-cadherin、Vimentin、EGFR蛋白表达情况,流式细胞仪检测各组细胞凋亡情况,比较组间差异。结果 各组药物作用均能不同程度抑制上皮间质化肺腺癌细胞H358增殖,E-cadherin表达呈上升趋势,Vimentin表达下降。其中EEHD联合吉非替尼组的细胞生长抑制率和细胞凋亡率显著高于吉非替尼单用组,E-cadherin蛋白表达率则显著高于吉非替尼单用组,而EGFR、Vimentin蛋白表达率显著低于吉非替尼单用组(P<0.05),EEHD与吉非替尼先后顺序作用组间差异无统计学意义。结论 EEHD与吉非替尼对上皮间质化的H358细胞具有联合抑制作用,白花蛇舌草可部分逆转H358细胞上皮间质化状态。     

吉非替尼联合培美曲塞和顺铂治疗晚期非小细胞肺癌的安全性和有效性

目的:比较单用培美曲塞/顺铂化疗或吉非替尼联合培美曲塞/顺铂化疗治疗晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的临床疗效及安全性,为临床应用提供参考。方法:选择标准一线化疗后复发的晚期NSCLC患者112例,其中联合治疗组52例接受培美曲塞/顺铂及吉非替尼治疗,化疗组60例仅采用培美曲塞和顺铂化疗,评价两组患者的临床疗效及不良反应。结果:联合组客观有效率（objective response rate,ORR）为36.5%,高于化疗组的18.3%（P=0.030）;两组疾病控制率（disease control rate,DCR）分别为71.2%和55.0%（P=0.035）;两组患者的中位无进展生存期（progression free survival,PFS）分别为8.7个月和6.7个月,差别有统计学意义（P=0.047）,但两组患者的中位总生存期（overall survival,OS）差别无统计学意义（P=0.265）。与治疗前相比,两组患者的肿瘤标志物均明显下降,但联合组的CEA和CYFRA21-1水平比化疗组更低（P<0.05）。联合组皮疹和腹泻的发生率高于化疗组（P<0.05）,两组之间其它不良反应的发生率无明显差别（P>0.05）。结论:晚期NSCLC患者一线化疗失败后,采用培美曲塞/顺铂化疗联合吉非替尼靶向治疗较单用化疗显示出更高的ORR和中位PFS,且不良反应可以耐受,值得临床推广运用。     

Gefitinib-induced disseminated intravascular coagulation in a patient with non-small cell lung cancer

In February 2005, Gefitinib （Iressa）, a small-molecular .epidermal growth factor receptor and tyrosine kinaseinhibitor, was approved in China as an anticancer agent for patients with advanced （local or metastatic） non-small cell lung cancer （NSCLC）, who failed prior chemotherapy. The common adverse events of the drug include acne-like skin rash, paronychia, pruritus, diarrhea, nausea/vomiting, anorexia, hepatitis, and hyperbilirubinemia.1 However, these adverse events are generally mild in severity and reversible on cessation of the treatment. Therefore, gefitinib has been regarded as a relatively safe agent,     

Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemotherapy in patients with advanced nonsmall cell lung cancer: evidence from an individual patient analysis

BACKGROUND:

Excision repair cross complementing 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) are molecular determinants that predict sensitivity or resistance to platinum agents and gemcitabine, respectively. Tailored therapy using these molecular determinants suggested patient benefit in a previously reported phase 2 trial. Here, we report an individual patient analysis of prospectively accrued patients who were treated with the “personalized therapy” approach versus other “standard,” noncustomized approaches.

METHODS:

Patients who had nonsmall cell lung cancer (NSCLC) with extranodal metastatic disease and an Eastern Cooperative Oncology Group performance status of 0/1 were accrued to 4 phase 2 clinical trials conducted at the H. Lee Moffitt Cancer Center: Trial A (first‐line carboplatin/gemcitabine followed by docetaxel), Trial B (docetaxel and gefitinib in patients aged ≥70 years), Trial C (combination therapy with carboplatin/paclitaxel/atrasentan), and Trial D (personalized therapy based on ERCC1 and RRM1 expression). Patients with low RRM1/low ERCC1 expression received gemcitabine/carboplatin, patients with low RRM1/high ERCC1 expression received gemcitabine/docetaxel, patients with high RRM1/low ERCC1 expression received docetaxel/carboplatin, and patients with high RRM1/high ERCC1 expression received vinorelbine/docetaxel. Patients who were treated on Trials A, B, and C were pooled together and analyzed as the “standard therapy” group. Patients accrued to Trial D were called the “personalized therapy” group. Individual patient data were updated as of February 8, 2011. Overall survival (OS) and progression‐free survival (PFS) were estimated using the Kaplan‐Meier method.

RESULTS:

There were statistically significant improvements between the personalized therapy group versus the standard therapy group in response (44% vs 22%; P = .002), OS (median: 13.3 months vs 8.9 months; P = .016), and PFS (median: 7.0 months vs 4.3 months; P = .03).

CONCLUSIONS:

The results from individual patient analyses suggest that ERCC1 and RRM1/tailored selection of first‐line therapy improved survival over standard treatment‐selection approaches. Cancer 2012. © 2011 American Cancer Society.     

Second‐line treatments after first‐line gefitinib therapy in advanced nonsmall cell lung cancer

Gefitinib is effective as first‐line therapy for advanced nonsmall cell lung cancer (NSCLC). However, after failure of gefitinib, it is unknown whether any second‐line regimens could lead to better outcomes. To study the influence of different second‐line antitumor regimens on the outcomes of patients with NSCLC after failure of first‐line gefitinib, we carried out a retrospective study in a tertiary referral medical center to investigate the prognosis of patients with NSCLC receiving second‐line antitumor treatment after gefitinib therapy. Clinical data and epidermal growth factor receptor (EGFR) mutational status of tumors were collected. A total of 195 patients with Stage IIIb or IV NSCLC receiving first‐line gefitinib and at least 1 subsequent line therapy were identified. A second‐line therapy with a platinum‐based combination or taxane‐containing regimen were associated with a higher therapy response, whereas a platinum‐based combination was linked to better overall survival. Ninety‐five patients had tumors with known EGFR mutation status; 61 had EGFR mutations and 34 had wild‐type EGFR. A second‐line therapy with a gemcitabine/platinum combination regimen resulted in better overall survival than erlotinib in patients with EGFR mutations (p = 0.035) but not in patients with wild‐type EGFR (p = 0.785). The study suggested that, after failure of first‐line gefitinib therapy, second‐line platinum‐based combination regimens were associated with a better overall survival than other regimens, including erlotinib. The survival benefit of platinum‐based combination regimens existed in patients with mutant EGFR but not wild‐type EGFR.     

EGFR基因突变及HER2/HER3蛋白表达水平与吉非替尼治疗晚期非小细胞肺癌疗效的关系

背景与目的:吉非替尼治疗非小细胞肺癌(NSCLC)的疗效不一,如何选择对吉非替尼敏感的患者,提高药物的疗效是临床中的难点。本研究探讨了中国人群中表皮生长因子受体(epidermal growth factor receptor,EGFR)的突变及HER2/HER3蛋白表达与吉非替尼治疗局部晚期或转移性NSCLC疗效的关系。方法:2002年5月至2005年2月,符合入组条件的106例患者每日口服250mg吉非替尼一次,直至疾病进展或出现不可耐受的毒副反应。收集吉非替尼治疗前的肿瘤组织。提取基因组DNA后,采用nest PCR技术扩增EGFR基因的18～24外显子,并从正反两个方向进行DNA测序和分析。同时采用免疫组化法检测84例肿瘤组织中的HER2/HER3蛋白的表达。结果:106例肿瘤标本中32例(30.2%)发生了突变。HER2高表达患者的有效率显著高于低表达的患者(36.8%vs.17.4%,P=0.044)。HER2/HER3的表达水平与疾病进展时间(TTP)及总生存期(OS)无关,但HER2/HER3高表达的患者生存期较低表达组略长(9.1个月vs.6.1个月,P=0.725;9.0个月vs.6.1个...     

Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy

BACKGROUND:

Gefitinib and erlotinib are commonly used for salvage therapy in patients with nonsmall cell lung cancer (NSCLC) who have progressed on prior therapies. Although both agents have similar structure and have demonstrated efficacy in NSCLC, gefitinib and erlotinib have not been directly compared in terms of efficacy and other clinical outcomes in patients with NSCLC who have failed prior chemotherapy. This prompted us to analyze the clinical outcomes between gefitinib‐treated and erlotinib‐treated patients with metastatic or recurrent NSCLC.

METHODS:

A total of 467 patients with metastatic or recurrent NSCLC who had progressed on prior therapies and received gefitinib or erlotinib therapy between January 2006 and December 2008 were retrospectively reviewed. By using a matched‐pair case‐control study design, 171 pairs of gefitinib‐treated and erlotinib‐treated patients were matched according to sex, Eastern Cooperative Oncology Group (ECOG) performance status, histologic type, and smoking history.

RESULTS:

The median age of all patients was 58 years (range, 20‐85 years), and the median ECOG performance status was 1 (range, 0‐3). Of 342 patients, 294 (86%) received an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor as second‐line or third‐line therapy, whereas the remaining 14% had received >2 prior chemotherapy regimens before starting EGFR TK inhibitor therapy. The confirmed overall response rate was 35.1%, and the disease control rate was 64%. With 13.2 months of follow‐up, the median overall survival (OS) for the total 342 patients was 12.4 months (95% confidence interval [95% CI], 10.66‐14.14 months), and the median progression‐free survival (PFS) was 3.2 months (95% CI, 2.65‐3.75 months). The overall response rates and disease control rates in the gefitinib‐treated and erlotinib‐treated groups were 38% versus 32.2% (P = .273) and 63.2% versus 64.9%, respectively (P = .677). There was no statistically significant difference noted with regard to OS (median, 12.6 vs 12.1 months; P = 0.99) and PFS (median, 4.6 vs 2.7 months; P = .06) between the gefitinib‐treated and erlotinib‐treated groups.

CONCLUSIONS:

This retrospective analysis shows that gefitinib and erlotinib appear to have similar antitumor activity in terms of response rate and OS in pretreated patients with metastatic or recurrent NSCLC. Further prospective studies are warranted to elucidate any potential differences in toxicity and in dose intensity between gefitinib‐ and erlotinib‐treated patients. Cancer 2010. © 2010 American Cancer Society.     

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most common cause oflung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is used for its treatment;however, drug resistance is a major obstacle. Expression of Met has been associated with both primary andacquired resistance to gefitinib, but the mechanisms regulating its expression are not fully understood. Recently,miRNAs such as miR-130a have been shown to play a role in gefitinib resistance, but importance in NSCLC andrelationships with Met have not been fully explored. Here we show that miR-130a is over-expressed in gefitinibsensitiveNSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Moreover, miR-130a expressionwas negatively correlated with that of Met. Further analysis revealed that over-expression of miR-130a increasedcell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expressionof miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in bothgefitinib-sensitive and -resistant NSCLC cell lines, suggesting that miR-130a overcomes gefitinib resistance.We also demonstrated that miR-130a binds to the 3’-UTR of Met and significantly suppresses its expression.Finally, our results showed that over-expressing Met could “rescue” the functions of miR-130a regarding cellapoptosis and proliferation after cells are treated with gefitinib. These findings indicate that the miR-130a/Metaxis plays an important role in gefitinib resistance in NSCLC. Thus, the miR-130a/Met axis may be an effectivetherapeutic target in gefitinib-resistant lung cancer patients.     

125I粒子植入联合吉非替尼治疗非小细胞肺癌的临床疗效及对免疫系统的影响

目的 探讨125I粒子植入联合吉非替尼治疗非小细胞肺癌的临床疗效及对免疫系统的影响.方法 选取53例非小细胞肺癌患者为研究对象,均接受125I粒子植入联合吉非替尼治疗.对所有患者进行疗效和不良反应评价,同时测定治疗前及治疗后1、3、6个月时患者外周血T淋巴细胞亚群、NK细胞、CIK细胞及相关免疫调节因子的水平变化.结果 治疗后1、3、6个月的有效率分别为54.72%、64.15%、75.47%.术后1例患者出现粒子脱靶和迁移,1例患者出现气胸,2例患者出现咯血,所有患者均未出现白细胞减少和放射性肺损伤,本组治疗未出现其他严重并发症.治疗后6个月患者的外周血CD4+、CD4+/CD8+、NK细胞水平均较治疗前升高(P<0.05),CD8+水平较治疗前降低(P<0.05).治疗后6个月患者的外周血TNF-α、IL-2、IL-4、IL-6、IL-10水平均较治疗前降低(P<0.05).结论 125I粒子植入联合吉非替尼治疗非小细胞肺癌的临床疗效较好,治疗后不良反应发生率较低,同时可以调节患者T淋巴细胞亚群、NK细胞及免疫调节因子的表达,改善患者的免疫功能.