Re-expression of TSLC1 in a non-small-cell lung cancer cell line induces apoptosis and inhibits tumor growth

The TSLC1 tumor-suppressor gene is silenced in a number of human cancer tissues and cell lines, including lung, prostate, liver, stomach, pancreatic, and breast cancers. Expression of TSLC1 in a non-small-cell lung cancer (NSCLC) cell line A549 suppresses tumorigenicity in nude mice. However, the molecular mechanism of TSLC1 action is not yet elucidated. In the present study, we show that the expression of TSLC1 from a recombinant adenovirus vector (Ad-TSLC1) inhibited cell proliferation and induced apoptosis in the NSCLC cell line A549. We also demonstrated that subcutaneous tumor growth in nude mice induced by A549 cells was suppressed to the extent of 70-80% by intratumoral injection of Ad-TSLC1. Re-expression of TSLC1 also resulted in activation of the apoptotic protease caspase-3, accompanied by the cleavage of its substrate poly (ADP-ribose) polymerase (PARP). The antiproliferative and pro-apoptotic activity of TSLC1 required the presence of the FERM-binding and PDZ-interacting motifs located in the cytoplasmic domain. Our results demonstrate the pro-apoptotic and oncosuppressive activity of TSLC1 protein, and suggest the potential of TSLC1 for gene therapy.     

Gefitinib in the treatment of advanced non-small-cell lung cancer

Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and their long-term prognosis remains poor, even after platinum-based chemotherapy. EGF receptor (EGFR)-targeted therapies, such as gefitinib, have been subject to comprehensive clinical development. Several Phase II and III trials have evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemo-naive patients. A Phase III trial in heavily pretreated advanced NSCLC patients, 90% of whom were refractory, demonstrated some improvement in survival with gefitinib compared with placebo; however, the difference was not statistically significant in the overall population. A second large Phase III trial in patients with pretreated advanced NSCLC (INTEREST) demonstrated the noninferiority of gefitinib in comparison with docetaxel for overall survival together with an improved quality of life and tolerability profiles. As a result, gefitinib is expected to have a large impact in the management of pretreated patients with NSCLC.     

吉非替尼单药治疗晚期非小细胞肺癌

目的观察吉非替尼单药治疗晚期非小细胞肺癌（NSCLC）的疗效和不良反应。方法对50例晚期NSCLC患者给予吉非替尼250mg／d口服治疗,观察疗效和不良反应,采用欧洲癌症研究和治疗组织生活质量调查核心问卷QLQ-C30和简明乏力量表（BFI）对患者的生活质量及临床症状的改善进行评价,观察疾病进展时间（TTP）和中位生存时间（MST）。结果50例晚期NSCLC患者中,无完全缓解者,部分缓解（PR）8例（16．0％）,临床获益率为60．0％,临床获益率与性别、病理类型及吸烟史有关。到随访截止日期,50例患者中,20例（40．0％）存活,其MST为13个月;30例死亡患者TTP为5个月,MST为6个月。PR患者MST为9个月。综合生活质量改善率为58．0％,乏力症状缓解率为52．6％,出现症状缓解的中位时间为15d。不良反应主要为Ⅰ、Ⅱ度皮疹和腹泻,对症处理后可缓解。3例既往因放疗而引起放射性肺炎的患者中,2例放射性肺炎加重。结论吉非替尼有明显抗肿瘤作用,能明显提高晚期NSCLC患者的生活质量,改善临床症状,不良反应可以耐受。     

Gefitinib treatment affects androgen levels in non-small-cell lung cancer patients

Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR, HER1/ErbB1) tyrosine kinase, has been shown to have clinical activity against non-small-cell lung cancers (NSCLCs), especially in women nonsmokers with adenocarcinomas. The aim of the present study was to clarify the relationship between androgen levels and gefitinib treatment in patients with advanced NSCLCs. Sera from 67 cases (36 men and 31 women) were obtained pretreatment and during treatment with gefitinib monotherapy (days 14-18) for examination of testosterone, dehydroepiandrosterone sulphate (DHEA), and dehydroepiandrosterone sulphate (DHEAS) levels. Testosterone and DHEA during treatment were significantly lower than the pretreatment values in both women and men, and the DHEAS levels during treatment were also significantly lowered in women. Gefitinib treatment significantly suppressed androgen levels, especially in women who had no smoking history. In addition, hormone levels in women responding to gefitinib were significantly lower during the treatment than in women who did not respond. Gefitinib-associated decrease in serum androgen levels may play a role in its clinical efficacy.     

吉非替尼在老年和行为状态差的非小细胞肺癌患者中的应用

老年或行为状态差(PS≥2)的非小细胞肺癌患者通常对化疗的耐受性较差.表皮生长因子受体酪氨酸激酶抑制剂--吉非替尼副作用轻,耐受性好,使得这一特殊群体可能从中获益.吉非替尼在PS=2～3的患者中有效率为13%～17%,疾病控制率为17.1%～41.6%.在老年患者中,疾病控制率为50%左右.副作用主要是工/Ⅱ级的皮肤病变和腹泻.本文对文献报道的吉非替尼治疗老年和行为状态差的非小细胞肺癌的临床研究进行了总结.     

去甲斑蝥素对人乳腺癌细胞系的凋亡诱导作用及bcl-2基因的表达

目的：探讨去甲斑蝥素抗肿瘤作用的分子机制。方法：用１０μｇ／ｍｌ去甲斑蝥素处理体外培养的人乳腺癌细胞素ＭＣＦ－７。处理后,在不同时间点,采用普通光镜、电子显微观察去甲斑蝥素对乳腺癌细胞的诱导凋亡现象。利用流式细胞仪分析凋亡细胞百分比,用蛋白印迹杂交方法对凋亡抑制基因ｂｃｌ－２的表达情况进行检测。结果：经１０μｇ／ｍｌ去甲斑蝥素处理１２ｈ后,可观察到ＭＣＦ－７细胞变形、出泡,从培养瓶底脱离。细胞染色和电子显微镜可观察到染色质浓聚、边集,且随着药物作用时间的延长,凋亡细胞百分比逐渐增加。与对照组相比,凋亡抑制基因ｂｃｌ－２的表达降低。结论：诱导肿瘤细胞凋亡可能是去甲斑蝥素抗肿瘤作用的分子机制之一。     

吉非替尼治疗男性晚期非小细胞肺癌59例报告

目的探讨吉非替尼单药治疗男性晚期非小细胞肺癌(NSCLC)的疗效及安全性。方法男性NSCLCⅣ期患者59例,其中腺癌、细支气管肺泡癌占86.4%,既往化疗2个方案以上者占66.1%。口服吉非替尼至病情进展或出现不可耐受不良反应。患者分别于治疗1个月、治疗3个月、治疗3个月以后每隔2个月复查。结果59例患者均可评价疗效,无完全缓解患者,部分缓解14例,稳定10例,进展35例,有效率为23.7%,稳定率为16.9%,疾病控制率为40.7%。中位肿瘤进展时间为1.8个月。中位生存时间为8.5个月,生存时间与最佳疗效及一般状况有关。1、2和3年生存率分别为42.4%、17.1%和13.3%。常见不良反应为皮肤改变和腹泻,多为1、2度。结论吉非替尼单药治疗男性晚期NSCLC疗效明确,疾病控制后患者生存时间延长,不良反应较易耐受,是二线、三线用药的良好选择。     

蝙蝠葛提取物对人肺癌细胞系A549诱导凋亡作用的研究

目的探讨蝙蝠葛提取物对人肺癌细胞系A549诱导凋亡和抗增殖作用及其机制,为开发抗肿瘤新中药提供实验依据。方法应用MTT法测定蝙蝠葛提取物对人肺癌细胞系A549的生长抑制作用;通过倒置显微镜、光学显微镜观察肿瘤细胞凋亡的形态学变化;采用流式细胞术检测A549细胞的凋亡率;应用免疫组织化学技术检测药物处理前后凋亡相关蛋白酶caspase-3、caspase-8、caspase-9的表达。结果 （1）MTT法检测结果：蝙蝠葛提取物对人肺癌细胞系A549有明显的抑制生长的作用,且呈现出浓度的依赖性;（2）倒置显微镜观察结果：实验组肿瘤细胞体积变小、变圆,核染色质凝集,细胞间连接疏松,贴壁能力减弱;（3）HE染色观察结果：实验组肿瘤细胞体积变小、变圆,核染色质浓缩或染色质块形成,有的细胞膜起泡形成凋亡小体;（4）流式细胞术检测结果显示：蝙蝠葛提取物可以诱导A549细胞发生凋亡,加药组出现亚二倍体峰。结论 （1）蝙蝠葛提取物在体外对人肺癌细胞系A549有显著的诱导凋亡作用;（2）蝙蝠葛提取物诱导凋亡作用机制可能通过上调caspase-3、caspase-8和caspase-9蛋白表达,经由细胞凋亡的死亡受体和线粒体通路完成凋亡的启动和执行;（3）蝙蝠葛提取物具有显著的体外抗肿瘤作用,有望开发成一种新的抗肿瘤药物。     

EMP INDUCES APOPTOSIS IN HUMAN LUNG CARCINOMA CELL LINE GLC-82

The possibility of health risks resulting from exposure to electric and magnetic fields provides a strong motivation to determine how such fields interact with cells. The short, intense electromagnetic pulse (EMP) produced by high-altitude nuclear explosions may radiate over many hundreds of miles. Basically, EMP consists of a pulse of radio-frequency waves with a nearly instantaneous rise in the electric and magnetic fields and a subsequent decline in the fields. EMP radiation may be repre…     

Gefitinib as front-line treatment in Chinese patients with advanced non-small-cell lung cancer

PURPOSE: This phase II single arm, open label study was designed to evaluate the efficacy and toxicity of oral gefitinib (250mg) daily in previously untreated patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Eligible patients had stage IIIB or IV NSCLC with adequate organ functions, and were chemona?ve. All eligible patients were treated with oral administration of 250mg of gefitinib until intolerable toxicity, disease progression or death occurred. Responses were assessed after every 8 weeks of therapy. RESULTS: For a total of 53 patients, the objective response rate (ORR) was 32.1% and overall disease control rate (DCR) was 52.8%. Median overall and progression-free survivals (PFS) were 9.4 (95% CI, 8.8-13.3) and 3.2 months (95% CI, 1.1-5.2) months, and 1-year survival rate was 41.5%. Patients with adenocarcinoma (n=35) had a higher response rate. Adenocarcinoma, female gender (n=24), and response to gefitinib were predictive factors for better survival. The most commonly seen adverse events (AEs) were skin toxicity (54.7%), diarrhea (43.4%) and nail change (16.9%). Most AEs were mild to moderate and considered manageable. Drug-related interstitial pneumonia was clinically diagnosed in four cases (7.5%). CONCLUSIONS: Oral gefitinib, as compared to conventional chemotherapy, has comparable effect but less toxicity as a first-line treatment in Chinese patients who have advanced NSCLC, especially in those with adenocarcinoma histology. A further phase III prospective study comparing gefitinib to standard chemotherapy to define the efficacy of gefitinib is appropriate in advanced NSCLC patients.     

Gefitinib in elderly and unfit patients affected by advanced non-small-cell lung cancer

Elderly and poor performance status advanced non-small-cell lung cancer (NSCLC) patients often tolerate chemotherapy poorly. Special approaches are needed for these patient populations. Gefitinib (Iressa) was used in 59 elderly and/or unfit NSCLC pretreated patients participating in a compassionate use programme showing some activity and good tolerability.     

黄腐酚对顺铂诱导H1650细胞凋亡的影响

目的 以顺铂为主的非小细胞肺癌化疗方案不断更新,目前研究旨在寻求疗效的放大及毒副作用的缩小.黄腐酚被证明有抗癌及保护正常细胞的作用.本实验主要探讨黄腐酚的不同给药方式对顺铂诱导人非小细胞肺癌细胞株H1650凋亡的影响.方法 采用CCK-8法检测黄腐酚、顺铂单用及先用低浓度黄腐酚干预,后补入顺铂对H1650细胞增殖的影响;使用流式细胞术分别分析先用黄腐酚后用顺铂、先用顺铂再补入黄腐酚2种干预方式对H1650细胞凋亡率或存活率的影响.结果 CCK-8检测结果显示,2μmol/L黄腐酚干预H1650细胞48 h后,继续给予20、40和80μmol/L顺铂干预24 h,抑制细胞增殖率分别为(13.16±1.06)%、(19.14±1.67)%和(28.17±2.79)%,均低于同浓度顺铂单纯干预24 h组的(18.96±3.02)%、(23.28±1.43)%和(39.79±3.44)%,P<0.05.流式细胞术检测结果显示,10、20和40μmol/L顺铂干预细胞24 h后,继续给予7〔(85.66±3.19)%、(74.62±2.98)%和(59.55±2.70)%〕或14μmol/L〔(82.04±2.88)%、(76.50±3.11)%和(61.76±3.01)%〕黄腐酚干预24 h,其细胞存活率明显高于同浓度顺铂单纯干预48 h组的(72.60±2.69)%、(56.98±3.80)%和(44.15±2.01)%,P<0.05.3μmol/L黄腐酚干预细胞24 h,弃培养液,更换10、20和40μmol/L顺铂再干预24 h,其细胞凋亡率分别为(29.79±3.78)%、(30.53±3.89)%和(39.48±4.98)%,明显高于顺铂单纯干预24 h组的(17.21±3.01)%、(14.53±2.99)%和(18.88±4.20)%,P<0.05.结论 黄腐酚直接有效保护顺铂对H1650细胞的杀伤,但低浓度黄腐酚的前期干预间接提高了顺铂对H1650细胞的凋亡率.     

Gefitinib therapy for non-small cell lung cancer

Opinion statement Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.     

Down-regulation of miR-150 induces cell proliferation inhibition and apoptosis in non-small-cell lung cancer by targeting BAK1 in vitro

Non-small-cell lung cancer (NSCLC) is one of the most common causes of cancer-related death. Our investigations show that miR-150 is a typical microRNA that is overexpressed in human NSCLC. We characterized the effects of miR-150 overexpression in NSCLC cells and found that down-regulation of miR-150 expression inhibited cell proliferation and induced cell apoptosis in vitro; additionally, up-regulation of miR-150 levels had the opposite effect on tumor growth and progression. Furthermore, we found that the mechanism of the miR-150 effects on NSCLC cells was associated with alterations in the expression of human BRI1-associated receptor kinase 1 (BAK1). miR-150 may function as an oncogene in NSCLC cells by directly targeting BAK1. Thus, these data highlight a novel molecular interaction between miR-150 and BAK1 and provide a novel strategy for NSCLC therapy via the down-regulation of miR-150 expression.     

吉非替尼与多西紫杉醇治疗晚期非小细胞肺癌的meta分析

 目的评价吉非替尼与多西紫杉醇作为晚期非小细胞肺癌（NSCLC）二线治疗的临床疗效及安全性。方法计算机检索PubMed、EMBASE、Cochrane Library、中国期刊全文数据库、中国生物医学文献数据库、中文科技期刊全文数据库和万方数据库,纳入吉非替尼与多西紫杉醇治疗既往接受过化疗的局部晚期NSCLC的临床随机对照试验（RCT）,依据Cochrane系统评价手册5.0.2质量评价标准进行质量评价,采用RevMan5.0软件进行meta分析。结果最终纳入4个RCT（2 257例）。meta分析结果显示,吉非替尼与多西紫杉醇相比,可以提高局部晚期NSCLC患者的客观缓解率、生活质量改善率（P＜0.05）;并且其3～4级不良反应发生率低（P＜0.05）。而在总生存率、症状改善率和无进展生存率方面,差异无统计学意义（P＞0.05）。结论吉非替尼用于治疗既往接受过化学治疗的局部晚期或转移性NSCLC的客观缓解率优于多西紫杉醇,而且患者生活质量改善显著,其药物耐受性和安全性更高,目前可作为一种有效的二线治疗药物积极推广应用,但生存期方面仍需进一步研究。     

Propofol induces endoplasmic reticulum (ER) stress and apoptosis in lung cancer cell H460

Propofol is one of the most commonly used intravenous anesthetic agents during cancer resection surgery. It can influence proliferation, motility, and invasiveness of cancer cells in vitro and in vivo. However, the role of the propofol in the lung cancer cells remains unclear. In this study, we demonstrated the effects of propofol on the proliferation and the apoptosis of lung cancer cell H460 by using colony formation assay and flow cytometry. Propofol also decreased tumor size and weight in established xenografted tumors. Furthermore, propofol-induced endoplasmic reticulum (ER) stress was determined by Western blot.     

吉非替尼治疗晚期复治性非小细胞肺癌的临床研究

目的探讨应用吉非替尼(IRESSA)治疗晚期非小细胞肺癌(NSCLC)患者的疗效及其对生活质量的影响。方法既往化疗失败的Ⅲb-Ⅳ期NSCLC患者41例,其中二线化疗失败者占85.4%(35/41)。IRESSA 250 mg口服,每日1次,服药至病情进展或出现不能耐受的不良反应。患者分别在治疗后1个月、2个月和以后每3个月复查。结果本组41例患者均可评价疗效,其中PR 18例,SD 14例,PD 9例,有效率为43.9%(18/41),疾病控制率(PR SD)为78.0%(32/41)。男性患者和女性患者的有效率分别为42.1%和45.5%(P>0.05)。至随访结束,41例患者中,有22例(53.7%)存活,其中位生存时间(MST)为10.1个月;19例死亡患者的疾病进展时间(TTP)为2.7个月,MST为5.0个月;PR患者的MST为13.3个月。全组患者症状改善率为78.0%。服药28 d,KPS评分提高20±5分,无Ⅲ-Ⅳ度毒性反应。结论IRESSA单药对化疗失败的晚期NSCLC疗效确切,并可用于一般状况评分较差的患者,其不良反应轻,是二三线用药的良好选择。     

吉非替尼治疗91例晚期非小细胞肺癌疗效分析

目的 总结表皮生长因子受体酪氨酸激酶抑制剂吉非替尼治疗91例晚期非小细胞肺癌患者的疗效、中位肿瘤进展时间（TTP）、中位生存期和毒副反应,分析与疗效、生存期可能相关的因素。方法 91例化疗失败的晚期非小细胞肺癌患者,中位化疗周期数为6（1～17）周期,68例（74．7％）患者至少经过二线方案化疗,疾病仍进展;Ⅳ期76例（83．5％）,其中42例（46．2％）至少有2个转移部位。口服吉非替尼剂量为250mg／d。运用SPSS11．5统计软件进行统计分析。结果 全组客观有效率为20．9％（19／91）,疾病控制率为63．7％（58／91）,症状改善率为72．7％（40／55）,ECOG评分稳定及改善为71．4％（65／91）。腺癌、至少接受二线方案化疗及出现皮肤毒性者与疾病控制率呈明显正相关（P值分别为0．04、0．02及0．00）。中位TTP 5．0个月（95％CI为3．26～6．74）,中位随访7．5（1～18．5）个月,1年生存率为56．4％。目前仍存活56例（61．5％）,其中29例（51．8％）仍处于疾病控制中,20例生存期已超过1年（12～18．5个月）。对生存有益的单因素为不吸烟、疾病控制、出现皮肤毒性及吉非替尼治疗过程中控制转移灶。经Cox回归分析发现,不吸烟、疾病控制是独立预后因素（P值分别为0．01和0．00）。毒副反应主要为Ⅰ、Ⅱ度皮肤毒性。结论 靶向治疗药物吉非替尼对传统治疗失败的晚期难治性非小细胞肺癌患者有明显疗效,有改善症状及延长生存期作用,且耐受性好。     

Gefitinib induces premature senescence in non-small cell lung cancer cells with or without EGFR gene mutation

Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 microM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild- type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 microM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.