冰片逆转小细胞肺癌顺铂耐药的研究

摘 要：［目的］ 评价冰片对小细胞肺癌（SCLC）顺铂（DDP）耐药的逆转作用及其对P糖蛋白（P-glycoprotein，P-gp）和小凹蛋白-1 (Caveolin-1)表达的影响。［方法］ 利用前期建立的SCLC DDP耐药细胞株LTEP-P/DDP，四甲基偶氮唑盐微量酶反应比色法（MTT）检测冰片和/或DDP的抗肿瘤活性，流式细胞仪检测细胞周期和凋亡率，Western blotting检测P-gp和Caveolin-1的表达。［结果］冰片联合DDP对LTEP-P/DDP-0.75 细胞的增殖抑制作用较单用DDP显著性增加（P<0.05），耐药逆转指数为2.246。LTEP-P/DDP-0.75细胞经冰片联合DDP处理细胞后，较单用DDP处理组的G0/G1期和S期降低，G2/M期升高，差异有显著性（P<0.05）。冰片和DDP联合处理后，LTEP-P/DDP-0.75细胞凋亡显著性上升（P<0.05），LTEP-P/DDP-0.75细胞Caveolin-1相比LTEP-P细胞显著性上升（P<0.05），冰片或DDP单独用药组Caveolin-1显著性变化，冰片联合联合DDP组相比对照组能显著性降低LTEP-P/DDP-0.75细胞Caveolin-1表达（P<0.05），而对P-gp无显著性抑制作用。［结论］ 冰片能在一定程度上逆转LTEP-P/DDP-0.75对DDP的耐药，其作用可能与抑制Caveolin-1表达有关。     

顺铂为主联合化疗治疗晚期非小细胞肺癌疗效分析

采用以顺铂为主的联合化疗方案治疗晚期非小细胞肺癌３６例。ＣＡＰ方案治疗２１例，无１例达完全缓解，７例达部份缓解，有效率为３３．３％；ＥＰ方案治疗１５例，１例达完全缓解，５例达部分缓解，有效率为４０％。３６例患者总有效率为３６．１％。化疗中出现的毒副反应主要是Ⅰ－Ⅱ级的骨髓抑制和消化道反应，未出现明显的肝肾功能损害，使用ＣＡＰ方案治疗时出现１例ＥＣＧ异常。     

基因芯片技术筛选非小细胞肺癌A549细胞顺铂耐药相关基因的研究

目的:采用基因芯片技术筛选人非小细胞肺癌(NSCLC)耐顺铂(DDP)A549细胞与A549细胞之间的差异表达基因,为进一步研究其耐DDP相关分子机制提供资料。方法:分别抽取耐DDPA549细胞与A549细胞的总RNA,采用逆转录的方法,制成cDNA链,并以2种荧光Cy5和Cy3标记后作为探针,与含有17101条人类16KcDNA基因表达谱芯片进行杂交,扫描荧光强度,并用计算机进行分析,寻找两组差异表达基因。结果:在17101条基因中,3株A549/DDP和3株A549细胞共同差异表达基因24条,其中上调基因12条,下调基因12条。结论:A549细胞发生DDP耐药过程中有多个基因参与,两者共同差异表达的24条基因可能参与其耐DDP分子机制。     

降低有氧糖酵解增强非小细胞肺癌耐药细胞对顺铂的敏感性

目的:探究顺铂耐药的非小细胞肺癌细胞糖代谢的特点及抑制有氧糖酵解对非小细胞肺癌细胞顺铂耐药细胞的影响及其机制。方法:通过梯度倍增浓度法建立非小细胞肺癌顺铂耐药细胞模型(A549/DDP);酶联免疫吸附试验(enzyme linked immunosorbent assay, Elisa)检测A549/DDP与A549细胞两组葡萄糖消耗量、三磷酸腺苷(adenosine triphosphate, ATP)释放量、乳酸生成及丙酮酸生成量的差异;CCK-8法(cell counting kit-8)检测2-脱氧葡萄糖(2-deoxyglucose, 2-DG)及顺铂处理后A549/DDP与A549细胞增殖能力的变化;Elisa检测2-DG处理A549/DDP细胞与A549细胞葡萄糖消耗量、ATP释放量、乳酸生成及丙酮酸生成量的差异;Elisa检测2-DG处理A549/DDP细胞与A549细胞后对非神经元性烯醇化酶(recombinant enolase 1,ENO1)、葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase, G6PD)、缺氧诱导因子-α...     

顺铂加卡铂治疗中晚期非小细胞肺癌的临床观察

全组共90例经病理学证实为中晚期的非小细胞肺癌。将病例随机分为三组,每组30例。均采用EP方案,第一组为足叶乙甙加顺铂,卡铂交替应用;第二组为足叶乙甙加顺铂;第三组为足叶乙甙加卡铂。90例均可评价疗效,第一组1例获完全缓解,13例获部分缓解,有效率达46.7％。第二组有效率为40％,第三组有效率为36.7％,第二、三组均无完全缓解病例。经统计学处理,三组疗效无显著差异。第一组胃肠道反应明显低于第二组,而骨髓抑制明显低于第三组,具有统计学意义。因此,第一组副作用比第二、三组低。     

紫杉醇加顺铂方案治疗晚期非小细胞肺癌

自1997年4月～2000年7月,我们应用国产紫杉醇加顺铂联合(TP)方案治疗27例晚期非小细胞肺癌(NSCLC)患者,获得了较好的疗效,现报告如下:1 资料和方法1.1 临床资料 全组27例中,男性21例,女性6例;年龄32～70岁,中位年龄52岁。所有病例经组织学或细胞学证实为NSCLC,其中腺癌15例、鳞癌11例、鳞腺癌1例。初治11例,复治16例。临床分期均为Ⅲ_B～Ⅳ期。近1月未接受过抗癌药物。治疗前查肝肾功能正常。预期生存3个月以上。有可测量的客观指标。Karnofsky评分均≥60分。1.2 治疗方法 国产紫杉醇135mg/m~2加入5％葡萄糖500ml中,静滴3小时,第1天;顺铂30mg/m~2,     

盖诺加顺铂治疗晚期非小细胞肺癌的临床观察

目的 观察国产去甲长春花碱（盖诺）加顺铂治疗非小细胞肺癌的临床治疗效果。方法 共有48例晚期非小细胞肺癌接受治疗，盖诺25mg/m^2，静滴，第1，8天；顺铂30mg/m^2，静滴1－3天；21天为一周期，2－3周期为一疗程。结果 全组CR5例，PR21例，SD17例，有效率54．2％，其中鳞癌为57．1％，腺癌为50．0％。主要毒性反应为血液学和消化道毒性。结论 国产盖诺加顺铂治疗NSCLC具有较好的临床治疗效果，与进口产品相似。     

国产紫杉醇联合顺铂治疗晚期非小细胞肺癌的临床观察

目的：观察国产紫杉醇(商品名为特素)联合顺铂治疗晚期非小细胞肺癌的近期疗效及其毒副作用。方法：特素135mg／m^2加入5％葡萄糖注射液500mL，静脉滴注，第1天，DDP20mg／m^2，静脉滴注，第1天～第5天。以上方案每28d为1周期，至少完成2周期。结臬：CR1例，PR18例，SD17例，PD6例。总有效率45．2％，主要毒副作用为恶心呕吐、血白细胞减少、脱发、轻度血小板及血红蛋白减少、轻度外周神经感觉异常、肝肾功能轻度损害。结论：国产紫杉醇联合顺铂治疗晚期非小细胞肺癌疗效较好，毒副作用可耐受，值得临床推广应用。     

安素泰联合顺铂方案治疗非小细胞肺癌疗效观察

目的：评价安素泰联合顺铂方案疗效、耐受性和不良反应。方法：安素泰和顺铂联合方案治疗晚期非小细胞的肺癌（NSCLC）26例。化疗方案以顺铂（DPP）75mg／m2静脉滴注，d1；安素泰（ANZATAX）135mg／m^2静脉滴注，d1，每21—28天重复。结果：全组共完成72个周期，有效率42．31％，一年生存率46．15％。常见的不良反应为骨髓抑制，发生率96．13％。其中Ⅰ度19．23％，Ⅱ度57．69％，Ⅲ度15．39％，Ⅳ度3．85％。结论：患者对安素泰和顺铂联合方案耐受良好，不良反应较轻，初步疗效令人满意，值得进一步研究。     

艾迪注射液对晚期非小细胞肺癌NP方案化疗的影响

Objective:To evaluate the effects of Aidi injection on vinorelbine plus cisplatin(NP) chemotherapy for advanced non-small cell lung cancer(NSCLC).Methods:Ninety eight patients with advanced NSCLC were randomized to receive either NP alone or NP plus Aidi injection every 3 weeks.The primary endpoint was overall survival;secondary endpoints included overall response rate,time to progression,and safety.Results:The median overall survival time was 11.6 months in NP plus Aidi-treated patients and 10.1 months in NP alone-treated ones,and 1-and 2-year survival rates were higher in the former(47% and 22%) than the latter(42% and 15%).The overall response rates in Aidi injection plus NP-treated patients tended to be higher but not statistically significant compared with NP alone-treated ones.The occurrence rates of grades 3 or 4 toxicities,e.g.fatigue,nausea,vomiting,appetite loss,leucopenia,thrombocytopenia and anemia,were lower in Aidi injection plus NP-treated patients than NP alone-treated ones,although not significantly different between them.Conclusion:Aidi injection promotes NP chemotherapeutic effects,reduces the toxicities,and improves the patients' tolerance to chemotherapy as well.It may be an effective adjunct to chemotherapy in patients with NSCLC.     

早期非小细胞肺癌预后相关因素分析

早期非小细胞肺癌患者首选手术治疗后，仍有部分出现了局部复发和／或远处转移。筛选出预后差的患者辅以综合治疗显得尤为重要。本文分析了近年来研究的一些早期非小细胞肺癌的预后因素。     

244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6–12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR.     

吉西他滨联合顺铂或卡铂方案一线治疗晚期非小细胞肺癌的疗效和毒性比较

Objective:To compare the efficacy and toxicity between gemdtabine plus cisplatin and plus carboplatin in firstline treatment of advanced non-small call lung cancer (NSCLC).Methods:Gemcitabine 1000 mg/m2 iv,d1,8;cisplatin 75 mg/m2 iv,d1,or 25 mg/m2 iv,d1-3;carboplatin AUC = 5 iv,d1;repeated every 21 days.Results:All 76 cases were available for objective response.Gemcitabine cisplatin (GCis) group:among 33 cases,CR 1 case,PR 13 cases,MR 3 cases,SD 7 cases,PD 9 cases,response rate,disease control rate,time to progress (TTP),median survival time (MST) and 1-,2-year survival rates were 42.42% (14/33),72.73% (24/33),5 months,14 months and 66.67% (22/33),12.12% (4/33),respectively;Gemcitabine carboplatin (GCarb) group:among 43 cases,PR 13 cases,MR 11 cases,SD 7 cases,PD 12 cases,the results while comparing with those of GCis group were 30.23% (13/43),72.09% (31/43),4 months,11 months and 48.84% (21/43),2.33% (1/43),respectively.Among them,only MST between the two groups had significant statistic difference (x2 = 2.45,P = 0.017).Mild to modest myelo-suppression as well as nausea and vomiting were observed.Conclusion:Both GCis and GCarb regimens had active and well-tolerated toxicity for advanced NSCLC.Cisplatin-based chemotherapy yields a substantial effective advantage over carboplatin-based regimens.Therefore,carboplatin and cisplatin are not equal-active and that cisplatin-based doublet regimens should remain the standard first-line therapy for patients with advanced NSCLC with good performance status.     

外泌体非编码RNA在非小细胞肺癌获得性耐药中的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌中最常见的类型,对化疗及靶向药物的获得性耐药严重影响NSCLC患者的生存期,NSCLC获得性耐药机制复杂,确切机制仍不清楚.肿瘤来源或与肿瘤相关的外泌体是参与调控NSCLC获得性耐药的重要机制,可以通过传递核酸、蛋白质等赋予敏感细胞耐...     

非小细胞肺癌非耐药蛋白基因表达与临床疗效关系的研究

目的探讨肺耐药蛋白（LRP）基因在非小细胞肺癌（NSCLC）气管镜活检组织或淋巴结活检组织中的表达与其临床疗效的关系。方法应用免疫组织化学S-P技术对19例非小细胞肺癌气管镜活检组织和28例肺癌转移的淋巴结活检组织进行LRP表达水平的检测,并观察其经NP方案化疗2个周期后的临床疗效。结果非小细胞肺癌LRP的表达阳性率为61.70%;在肺腺癌和肺鳞癌中的表达阳性率分别为76.92%和42.86%;LRP在两组间的表达有显著性差异（P〈0.05）。LRP表达水平在TNM分期中差异无显著性（P〉0.05）;经2个周期标准NP方案化疗后总有效率为42.55%,其中LRP表达阳性和阴性的临床有效率分别为24.14%和72.22%,两组间存在显著性差异（P〈0.05）。结论LRP在非小细胞肺癌中存在不同程度的表达,阳性者化疗疗效明显高于阴性者。     

改良的多西紫杉醇联合顺铂3周方案一线治疗晚期非小细胞肺癌

背景与目的：目前临床上广泛应用多西紫杉醇联合顺铂作为晚期非小细胞肺癌（NSCLC）的一线化疗方案,但传统3周方案毒副反应较大。因此本研究为比较多西紫杉醇联合顺铂改进的3周方案与传统3周方案一线治疗晚期NSCLC的疗效及毒副反应。方法：68例经组织学或细胞学确诊的ⅢB或Ⅳ期NSCLC患者,随机分为两组分别接受改进方案（A组）和传统3周方案（B组）化疗。A组：多西紫杉醇总剂量按75 mg/m^2,分两次分别于第1、8天,静脉滴注顺铂25 mg/（m^2.d）,静脉滴注,第1天~第3天,每3周重复;B组：多西紫杉醇75 mg/m^2,静脉滴注,第1天,顺铂用法同A组,每3周重复。2周期后评价疗效与毒副反应,并随访1年生存率。结果：两组均无CR,A组PR 10例,SD 20例,PD 4例,总有效率为29%;B组PR 11例,SD 20例,PD 3例,总有效率为32%;A组1年生存率为38%,B组1年生存率为35%,两组疗效（P=0.793）及1年生存率（P=0.801）差异无显著性。中性粒细胞Ⅲ/Ⅳ度减少A组18%;B组47%,两组差异有显著性（P=0.010）。结论：多西紫杉醇联合顺铂改进的3周方案一线治疗NSCLC与传统3周方案相比,疗效相似,但血液学毒性明显下降,耐受性好。     

Triplet chemotherapy with vinorelbine,gemcitabine, and cisplatin for advanced non-small cell lung cancer: a phase II study

We conducted a phase II trial of triplet chemotherapy consisting of vinorelbine, gemcitabine, and cisplatin in patients with advanced non-small cell lung cancer to assess its efficacy and toxicity. Thirty-three patients with chemotherapy-naïve stage IIIB disease (n=8), stage IV disease (n=23), or recurrence after surgical resection (n=2) were given intravenous infusions of vinorelbine 25 mg m⁻², gemcitabine 1000 mg m⁻², and cisplatin 40 mg m⁻² on days 1 and 8 at 3-week intervals. There were 16 partial responses, and the objective response rate was 48% (95% confidence interval: 31–66%). The median survival time was 13.5 months (95% confidence interval: 10.6–16.4 months), and the one-year survival rate was 61%. Grade 4 haematologic toxicity consisted of neutropenia in 72% of patients, and febrile neutropenia occurred in 42% of the patients. There was one toxic death, and it was attributed to neutropenic fever and haemoptysis. Autopsy revealed diffuse pulmonary haemorrhage secondary to bacterial abscesses and vasculitis in both lungs. The common nonhaematologic toxicities included grade 2–3 nausea (39%) and vomiting (18%). Triplet chemotherapy containing vinorelbine, gemcitabine, and cisplatin is effective in the treatment of chemo-näive patients with advanced non-small cell lung cancer, but produces unacceptable frequent febrile neutropenia.British Journal of Cancer (2002) 87, 1360–1364. doi:10.1038/sj.bjc.6600658 www.bjcancer.com© 2002 Cancer Research UK     

B细胞淋巴瘤/白血病-2在非小细胞肺癌中的表达与表皮生长因子受体抑制剂获得性耐药的关系

目的探讨非小细胞肺癌(NSCLC)患者在表皮生长因子受体(EGFR)抑制剂治疗发生耐药前后肺癌组织标本中B细胞淋巴瘤/白血病(bcl-2)表达的变化,明确bcl-2表达与EGFR抑制剂获得性耐药的关系。方法收集北京大学深圳医院2004年至2011年经吉非替尼片或盐酸厄洛替尼片治疗的23例NSCLC患者的系列肺癌组织标本。建立组织芯片,以免疫组化的方法检测bcl-2的表达情况,同时比较产生耐药前后bcl-2表达的变化。结果 23例标本耐药前bcl-2表达阳性例数为5例,阳性率为21.7%。耐药后bcl-2表达阳性例数为12例,阳性率为52.2%。两者比较,差异有统计学意义(X2=4.57,P=0.032)。表皮生长因子酪氨酸激酶抑制剂(EGFR-TKI)治疗后出现获得性耐药的患者,bcl-2较耐药前出现明显上调。结论 bcl-2介导的抗凋亡功能增强在EGFR-TKI获得性耐药的发生中可能起到了重要作用。     

重组人血管内皮抑素联合多西紫杉醇和顺铂治疗晚期非小细胞肺癌的临床观察

目的观察重组人血管内皮抑素(恩度)联合多西紫杉醇和顺铂方案(TP)治疗晚期非小细胞肺癌(NSCLC)的近期临床疗效和毒副反应。方法经病理学证实的98例ⅢB～Ⅳ期NSCLC患者随机分为试验组52例,对照组46例,试验组接受恩度联合多西紫杉醇和顺铂方案治疗,对照组单用多西紫杉醇和顺铂方案化疗,用药1周期后评价毒副反应,至少完成2周期治疗后评价疗效。结果试验组有效率为50.0%,临床受益率为78.8%;对照组的有效率为30.4%,临床受益率为58.7%,差异有统计学意义(P<0.05)。毒副反应主要有白细胞减少、血小板减少、恶心、呕吐,肝功损害和肌肉关节痛等,两组比较差异无统计学意义(P>0.05)。结论恩度联合多西紫杉醇和顺铂方案一线治疗晚期NSCLC近期疗效优于单用多西紫杉醇和顺铂方案治疗,且未增加化疗的毒副反应,安全性较好,值得临床推广使用和进一步深入观察。