低分子肝素对卵巢肿瘤化疗诱导凝血功能活化的影响

目的:研究化疗前应用单一剂量低分子肝素对卵巢癌凝血功能的影响。方法:选择30例卵巢癌患者为单纯化疗组,20例卵巢癌患者为化疗+低分子肝素组,分别检测化疗前和化疗后1、24和48 h血浆纤维蛋白原以及D-二聚体的含量。结果:单纯化疗组化疗后血浆纤维蛋白原含量均低于化疗前,其中化疗后24 h与化疗前相比,差异有统计学意义,P<0.01;D-二聚体水平化疗后显著高于化疗前,其中化疗后24和48 h与化疗前相比,差异均有统计学意义,P<0.01。化疗+低分子肝素组化疗后血浆纤维蛋白原含量也低于化疗前,其中化疗后24和48 h与化疗前相比,差异均有统计学意义,P<0.01;D-二聚体水平化疗后与化疗前相比升高不明显,差异无统计学意义,P>0.05。结论:化疗能显著促进卵巢癌患者凝血和纤溶水平的升高。化疗前应用单一剂量的低分子肝素能抑制凝血功能的活化。     

参麦注射液联合化疗治疗晚期恶性肿瘤疗效观察

目的:观察参麦注射液与化疗联用对中晚期癌症患者的治疗效果。方法:将56例中晚期癌症患者随机分为参麦联合化疗组及单纯化疗组。结果:参麦联合化疗组与单纯化疗组近期疗效差异无显著性(P≥0.05)。参麦联合化疗组生活质量明显高于单纯化疗组;毒性反应两组存在明显区别,单纯化疗组明显高于参麦联合化疗组。结论:参麦注射液与化疗联用对中晚期癌症患者有减低毒性反应的作用,并且提高了生活质量。     

肿瘤免疫治疗和化疗的协同效应及其作用机制

近年来肿瘤治疗领域受到关注的热点之一是免疫治疗与化疗的联合应用,大量基础与临床的研究结果表明,恰当的免疫化疗（chemoimmunotherapy） 能够取得较单一疗法更优的抗肿瘤效果,超越了以往认为化疗对免疫系统具有抑制作用、免疫治疗与化疗难以一起应用的传统观念。免疫化疗具有协同抗肿瘤效果的机制是多方面的,化疗可通过增强肿瘤细胞免疫原性、去除免疫抑制以及调节免疫应答反应等方式增强免疫治疗效果;另外,免疫治疗能够逆转肿瘤细胞的化疗耐药性,从而提高肿瘤细胞对化疗药物的敏感性并降低化疗的毒性作用等。目前,肿瘤免疫治疗与化疗协同作用的机制尚未完全清楚,相信通过其相关机制的不断阐明,将进一步提高免疫化疗的抗肿瘤效果并推动其临床应用。     

102例术后乳腺癌辅助化疗后贫血相关因素分析

[目的]探讨乳腺癌术后辅助化疗后贫血发生的相关因素.[方法]回顾性分析102例乳腺癌辅助化疗病人化疗前及每周期化疗后血红蛋白值,按分期分组观察每周期化疗后贫血发生率;按手术方式分组观察每周期化疗后贫血发生率;按化疗前血红蛋白水平分组观察每周期化疗后贫血发生率.[结果]Ⅰ、Ⅱ、Ⅲ期病人,化疗后贫血发生率无显著性差异(P＜0.05),乳房切除术的病人,贫血发生率高于乳房保留术的病人(3周期后P＜0.05,4周期后P＜0.01),化疗前血红蛋白水平低于110g/L的病人,与化疗前血红蛋白水平高于等于110g/L的病人相比,化疗后贫血发生率升高;化疗前血红蛋白水平＜120g/L的病人,与化疗前血红蛋白水平高于等于120g/L的病人相比,化疗后贫血发生率升高.[结论]乳腺癌术后接受辅助化疗的病人,贫血发生率与临床分期无关,与手术方式有关.     

乳腺癌COX-2和MMP-2的表达与新辅助化疗的关系

目的研究COX-2、MMP-2在乳腺癌新辅助化疗前后的表达变化,及其与新辅助化疗疗效的关系。方法应用免疫组织化学法检测48例乳腺癌新辅助化疗前后标本中COX-2、MMP-2的表达。结果新辅助化疗有效率为70.8%。化疗前后COX-2表达变化显著,由化疗前的62.5%降到化疗后的41.7%,(P<0.05);MMP-2表达无明显变化。化疗前后COX-2表达与MMP-2正相关,(P<0.05)。新辅助化疗前COX-2表达阳性者,化疗效果差(P<0.05),MMP-2表达与化疗疗效无关,(P>0.05)。结论COX-2可作为指导乳腺癌化疗并预测化疗敏感性的分子生物学指标,而MMP-2尚不能预测化疗疗效。     

肿瘤化疗患者营养不良现状及研究进展

我国关于肿瘤化疗患者的症候群研究逐年增多,大量研究表明,大部分肿瘤化疗患者存在恶心、呕吐、食欲下 降的副反应,这些症状导致肿瘤化疗患者整体生活质量较低,且极易造成肿瘤化疗患者体重下降与营养不良。营养状况不 仅直接影响着肿瘤化疗患者生活质量的好坏,而且与其治疗效果、并发症和临床结局密切相关,因此,肿瘤化疗患者的营 养状况,具有重要的临床研究价值与意义。本文针对肿瘤患者化疗期营养不良的发病病因及发病机制、我国肿瘤患者化疗 期患者的营养状况现状、营养不良对肿瘤化疗患者的影响、以及营养筛查与评估工具的临床应用现状等方面,进行了综述, 以期引起临床对于肿瘤化疗期患者营养状况的关注与重视,进而加强此类患者的营养支持与治疗;以期为临床实际工作中, 正确选择及使用营养状况的筛查与评估工具提供参考,预防肿瘤化疗期患者营养不良的发生,达到改善其营养状况的目的, 提高肿瘤化疗患者的生活质量,最终改善肿瘤化疗患者的临床结局。     

榄香烯联合化疗治疗恶性肿瘤的疗效与不良反应观察

目的 观察榄香烯联合化疗与单纯化疗治疗恶性肿瘤的血常规、肝肾功能变化、疗效及不良反应.方法 62例恶性肿瘤患者分为两组,榄香烯联合化疗组(28例)采用榄香烯注射液400 mg/d,同时联合化疗;单纯化疗组(34例).各组中相同肿瘤类型采取相同的化疗方案.结果 榄香烯联合化疗组与单纯化疗组治疗总有效率分别是60.7％和41.2％ (P ＜0.05).榄香烯联合化疗组治疗后白细胞、血小板计数明显高于单纯化疗组(P＜0.05);与治疗前比较,联合化疗组的白细胞、血红蛋白和血小板差异均无统计学意义(P＞0.05),单纯化疗组则差异均有统计学意义(P＜0.05).联合化疗组ALT、AST、Cr、BUN治疗前后无明显变化,单纯化疗组ALT、Cr治疗后有所升高,与联合化疗组比较差异有统计学意义(P＜0.05).在生活质量改善及不良反应方面,联合化疗组优于单纯化疗组(P＜0.05).结论 榄香烯联合化疗可以提高抗肿瘤疗效,减轻化疗不良反应,改善生活质量.     

非小细胞肺癌化疗、热化疗前后白细胞介素-2、-6的变化

目的观察化疗、热化疗对非小细胞肺癌（NSCLC）患者白细胞介素（IL）-2、IL-6水平的影响。方法67例NSCLC患者分为化疗组35例,热化疗组32例,观察其在治疗前后IL-2、IL-6的变化,并与健康对照组进行比较。结果治疗前化疗组与热化疗组IL-2、IL-6差异均无统计学意义（P〉0．05）;而两组与对照组比较差异有统计学意义（P〈0．05）。化疗组和热化疗组治疗后与治疗前比较IL-2、IL-6的变化差异有统计学意义（P〈0．05）;治疗后热化疗组与化疗组间差异亦有统计学意义（P〈0．05）。结论热化疗较单纯化疗明显提高IL-2、IL-6的水平,热化疗对NSCLC患者免疫状态干预明显。     

包埋式化疗泵治疗中晚期肺癌的临床研究

 目的 建立一种对肺癌晚期病人的有效治疗方法,探讨与传统经静脉化疗相比运用包埋式化疗泵的效果及由此产生的并发症及化疗后对机体的影响情况。方法 本研究以肺癌不能手术者为研究对象,分为两组,每组50例,包埋式化疗泵组（试验组）和静脉全身化疗组（对比组）。包埋式化疗泵组将化疗药物注入泵体。静脉全身化疗组将药品按常规方法配制后经静脉输入。结果 试验组与对照组比较肿瘤缩小情况差异有统计学意义（P<0.05）,试验组总有效率优于对照组。患者化疗后一般状态卡氏评分试验组与对照组比较差异有统计学意义（P<0.05）,试验组优于对照组。白细胞化疗后7天及14天时试验组与对照组相比较差异有统计学意义（P<0.05）。CD4/CD8、NK细胞化疗后7天及14天时试验组与对照组相比较差异有统计学意义（P<0.05）。结论 与传统的经静脉化疗相比,运用包埋式化疗泵缓慢灌注化疗其肿瘤缩小程度明显大于经静脉化疗组。化疗后患者的一般状态、白细胞减少情况、骨髓抑制及免疫功能情况均优于经静脉化疗组。     

乳腺癌COX-2、P-gp的表达与新辅助化疗的关系

目的:研究COX-2、P-gp在乳腺癌新辅助化疗前后的表达变化,及其与新辅助化疗疗效的关系.方法:应用免疫组织化学法检测48例乳腺癌新辅助化疗前后标本中COX-2、P-gp的表达.结果:新辅助化疗有效率为70.8%.化疗前后COX-2表达变化显著,由化疗前的62.5%降到化疗后的41.7%,P<0.05;P-gp表达无明显变化.化疗前后COX-2表达与P-gp正相关,P<0.05.新辅助化疗前COX-2、P-gp表达阳性者, 化疗效果差,P<0.05.结论:COX-2、P-gp可作为指导乳腺癌化疗并预测化疗敏感性的分子生物学指标.     

多西他赛与吉非替尼不同时序应用对人肺腺癌细胞的作用

目的 探讨多西他赛与吉非替尼不同时序应用对人肺腺癌细胞A549和PC-9的生长影响及其细胞学机制。方法 qPCR-HRM法检测人肺腺癌细胞EGFR和K Ras基因突变,MTT法检测细胞增殖, Western blotting检测细胞信号蛋白及磷酸化表达,FCM法检测细胞周期变化。结果 人肺腺癌A549细胞为EGFR基因野生型,PC-9细胞为EGFR第19外显子突变型。多西他赛和吉非替尼单药或联合用药均能抑制A549和PC-9细胞生长,呈浓度依赖性。多西他赛对A549和PC-9细胞生长的半数抑制浓度（IC₅₀）分别为5.24×10^-7和2.13×10^-8mol／L,吉非替尼分别为1.28×10^-5和4.58×10^-8mol／L。在IC₅₀浓度时,多西他赛序贯吉非替尼对A549和PC-9细胞的生长抑制率分别为60.00%和57.45%,均较单药组明显增高（P＜0.05）;而同时用药只对PC-9细胞有增效作用,抑制率为53.46％,较单药组明显增高（P＜0.05）。多西他赛表现为增强A549、PC-9细胞EGFR和ERK磷酸化,吉非替尼表现为抑制,两药均抑制PC-9细胞IGF-1R磷酸化。多西他赛序贯应用吉非替尼显著抑制EGFR和ERK磷酸化,两药同时应用对抑制PC-9细胞的IGF-1R磷酸化具有增强作用。多西他赛将A549及PC-9细胞阻滞在G₂期,吉非替尼将PC-9细胞明显阻滞在G₁期。结论 多西他赛序贯吉非替尼能够抑制EGFR野生型和突变型的A549及PC-9细胞生长,且呈增效作用,可能与影响细胞EGFR和ERK磷酸化有关;两药同时应用仅对PC-9细胞具有增效作用,可能与IGF-1R磷酸化抑制有关;不同时序应用的效果均可能与细胞周期相关。     

培美曲塞和吉非替尼不同时序应用对人肺腺癌细胞的作用和机制

目的 探讨培美曲塞与吉非替尼不同时序应用对肺腺癌细胞A549和PC-9生长及凋亡的影响, 并阐述其可能机制。方法 MTT法检测各组细胞的增殖抑制情况,流式细胞仪检测各组细胞凋亡及细胞周期分布,Western印迹法检测对EGFR下游信号通路及TS酶蛋白水平表达的影响。结果 培美曲塞序贯吉非替尼、培美曲塞同步联合吉非替尼对PC-9和A549细胞增殖抑制率及凋亡率较单药组均提高（P<0.05）,培美曲塞可以提高EGFR、AKT 、ERK磷酸化水平,而吉非替尼表现为抑制作用, 同时吉非替尼降低TS酶表达。培美曲塞序贯吉非替尼,培美曲塞同步联合吉非替尼抑制EGFR、AKT 、ERK磷酸化水平较单药更强。吉非替尼主要将PC-9、A549细胞阻滞在G0/G1期;培美曲塞主要将细胞阻滞在S期。培美曲塞序贯吉非替尼、培美曲塞同步联合吉非替尼较其他组G2/M期细胞比例提高（P<0.05）。结论 培美曲赛序贯吉非替尼、培美曲赛同步联合吉非替尼在PC-9、A549细胞中均起到协同增效作用,且培美曲赛序贯吉非替尼协同作用更为显著,可能主要与培美曲赛诱导EGFR、AKT 、ERK磷酸化及吉非替尼降低TS酶作用有关。     

Combined effects of EGFR and Hedgehog signaling pathway inhibition on the proliferation and apoptosis of pancreatic cancer cells

In the present study, we established a new experimental model to investigate the effects of EGFR targeting by RNAi, and the synergistic actions between the hedgehog (Hh) and EGFR signaling pathways on the proliferation and apoptosis in pancreatic cancer cells. Three human pancreatic cancer cell lines expressing EGFR shRNA were established, and gene expression inhibition was assessed in these lines using RT-PCR and western blot analysis. The effects of EGFR RNAi and Hh inhibition on cell proliferation and apoptosis were explored in?vitro and in?vivo. We observed that EGFR RNAi notably inhibited cell proliferation and colony formation, induced apoptosis and markedly decreased xenograft tumor growth. Furthermore, EGFR RNAi significantly enhanced cyclopamine sensitivity both in?vitro and in?vivo, and a synergistic decrease of both AKT and ERK phosphorylation was observed. The present study demonstrates that combined inhibition of both EGFR and Hh signaling pathways could establish a more promising antitumor approach than inhibiting each singly, and that there is a possible synergistic effect for Hh and EGFR signaling pathways on ERK and AKT phosphorylation.     

多西他赛与吉非替尼序贯应用对人肺腺癌细胞H1975存活及凋亡通路的研究

背景与目的表皮生长因子受体(epidermal growth factor receptor,EGFR)酪氨酸激酶抑制剂(tyrosinekinase inhibitors,TKIs)被用于治疗进展性晚期非小细胞肺癌(non-small cell lung cancer,NSCLC),然而最初接受EGFR-TKIs治疗有反应的患者,大部分会在10个月左右出现获得性耐药。绝大多数报告称T790M的突变是产生获得性耐药的主要原因,约占获得性耐药的50%。本研究旨在探索多西他赛和吉非替尼序贯应用对肺腺癌细胞H1975增殖和凋亡通路的作用。方法 M法检测细胞的增殖。等效线图法和联合指数(combination index,CI)法评估多西他赛和吉非替尼序贯作用的效价。流式细胞术检测细胞凋亡和周期分布,Hoechest 33258染色法检测凋亡形态。化学比色发光法检测Caspases的活性。结果等效线图法和联合指数法均显示多西他赛序贯吉非替尼组较其它序贯作用组明显抑制了细胞增殖,增加了细胞的凋亡。细胞周期分布实验结果显示与吉非替尼序贯多西他赛组主要把细胞抑制在G0/G1期相比较,多西他赛序贯吉非替尼组主要把细胞抑制在G2/M期。在肺腺癌H1975中,所有序贯模型组都主要通过活化Caspase-8/Caspase-3来诱导激活细胞凋亡通路。结论先用多西他赛再用吉非替尼治疗模式可能是TKIs耐药后T790M突变肺癌的一个新选择。     

Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines

The epidermal growth factor receptor (EGFR) is considered an important therapeutic target in pancreatic cancer, but it is currently impossible to identify those patients who are most likely to benefit from EGFR-directed therapy. We examined the biological effects of the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in a panel of nine human pancreatic cancer cell lines. The drug strongly inhibited DNA synthesis and induced low levels of apoptosis at clinically relevant concentrations in a subset of three of the lines (L3.6pl, BxPC3, and Cfpac1). Sensitivity to gefitinib correlated directly with ligand [transforming growth factor-alpha (TGF-alpha)] expression (r(2) = 0.71, P = 0.004) but not with surface EGFR expression. The gefitinib-sensitive cells displayed constitutive baseline EGFR phosphorylation, whereas the gefitinib-resistant cells did not. Exposure to gefitinib or a small interfering RNA construct specific for TGF-alpha reversed the constitutive EGFR phosphorylation and downstream target [extracellular signal-regulated kinases (ERK), AKT] phosphorylation in the gefitinib-sensitive cells but had no effects on ERK or AKT phosphorylation in gefitinib-resistant cells. Baseline EGFR phosphorylation was lower in a subclone of L3.6pl selected for low TGF-alpha expression, and these cells were also resistant to gefitinib-mediated growth inhibition. Gefitinib blocked the growth of tumor xenografts derived from L3.6pl cells but had no effect on the growth of tumors derived from EGFR-independent MiaPaCa-2 cells. Together, our data show that TGF-alpha expression identifies a subset of human pancreatic cancer cells that is dependent on EGFR signaling in vitro and in vivo. Quantification of TGF-alpha expression may therefore represent an effective means of identifying EGFR-responsive primary tumors.     

Small cell lung cancer cells express EGFR and tyrosine phosphorylation of EGFR is inhibited by gefitinib ("Iressa", ZD1839)

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839) has demonstrated anti-tumor activity in non-small cell lung cancer (NSCLC) and has been approved in over 20 countries. NSCLC has been reported to express high levels of EGFR. However, gefitinib appears to be more effective against adenocarcinoma than squamous cell carcinoma, the latter expressing more EGFR. In the present study, we evaluated the effect of gefitinib against the small cell lung cancer (SCLC) cell lines NCI-H82, NCI-H209, NCI-H510, NCI-H526 and NCI-H660. SCLC has been reported to express a low to undetectable level of EGFR. We compared the effects of gefitinib between cell lines with detectable and undetectable EGFR expression. First, we evaluated expression levels of EGFR and HER2/neu by Western blotting and immunoprecipitation respectively; EGFR protein was detected in two of the five SCLC cell lines, whereas HER2/neu was not detected in any. Next, we analyzed expression levels of phosphorylated ERK1/2 and compared these results with EGFR (HER-1/ErbB1) and HER2/neu (ErbB2) expression levels, as EGFR conducts signals through Ras-Raf-MAPK pathway; gefitinib inhibited phosphorylation of ERK1/2 by EGF addition in cell lines with detectable and undetectable EGFR expression. These data suggest that gefitinib is potentially effective against cancers with low EGFR expression such as SCLC.     

MEK抑制剂在EGFR-TKI靶向治疗非小细胞肺癌中的作用

非小细胞肺癌是最常见的肺癌,最常见的基因突变是EGFR突变,EGFR-TKI已被用于治疗含这类突变的患者。然而,随着治疗进展,患者逐渐出现耐药性导致治疗失败。主要原因是EGFR信号通路下游重新激活,其中RAS/RAF/MEK/ERK和PI3K/AKT/PKC途径最重要。ERK1/2信号再激活可产生对EGFR抑制剂的抗性。目前临床研究已经发现,MEK抑制剂可以抑制ERK磷酸化,从而阻止随后的MAP激酶下游磷酸化,并因此诱导肿瘤活动的退化和停滞。大量试验表明,ERK途径的持续激活有助于获得吉非替尼耐药性。MEK抑制剂还可以诱导细胞周期阻滞和凋亡。本文总结了MEK抑制剂和EGFR-TKI的作用及其在NSCLC治疗中的作用,为肺癌分子靶向治疗提供了新思路。     

Lack of AKT activation in lung cancer cells with EGFR mutation is a novel marker of cetuximab sensitivity

Epidermal growth factor receptor (EGFR) mutation is the best marker of sensitivity to the EGFR tyrosine kinase inhibitor gefitinib, but a marker for the anti-EGFR antibody cetuximab has not been identified in lung cancer. The present study investigated markers for sensitivity to cetuximab. Sensitivity to cetuximab and gefitinib was compared with EGFR expression, EGFR and KRAS mutation, and EGFR gene copy numbers in lung cancer cell lines. We also studied the effect of these agents on the activation of EGFR, ERK, AKT, and STAT3 in cetuximab-sensitive and -resistant cell lines. We found one cetuximab-sensitive cell line with EGFR mutation among 19 lung cancer cell lines. Analysis of molecules downstream from EGFR revealed that AKT phosphorylation was suppressed in this cell line. Augmentation of AKT phosphorylation by transfection of a plasmid induced resistance to cetuximab. Acquisition of cetuximab resistance was associated with AKT activation in this cell line, while pharmacological inhibition of AKT markedly enhanced the growth inhibitory effect of cetuximab. Dephosphorylation of AKT in association with EGFR mutation is a candidate marker for sensitivity to cetuximab, and combined use of an AKT pathway inhibitor with cetuximab could be a novel therapeutic strategy for lung cancer.     

Schedule-dependent antitumor activity of the combination with erlotinib and docetaxel in human non-small cell lung cancer cells with EGFR mutation, KRAS mutation or both wild-type EGFR and KRAS

Erlotinib is used as a standard treatment for recurrent advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations in NSCLC have been shown to be a predictive factor of erlotinib, although the relationship between K-ras oncogene (KRAS) mutations and erlotinib resistance is controversial. Recently, in vitro sequence-dependent interactions of erlotinib and docetaxel have been studied on as a novel therapeutic approach against NSCLC. The purpose of the present study was to determine the optimum novel regimen of erlotinib and docetaxel against NSCLC cells which have EGFR mutation (HCC827 cells), KRAS mutation (A549 cells) or both wild-type (NCI-H292 cells). First, we analyzed the effects of in vitro combination for cell proliferation-inhibition using a combination index. In all cell lines, docetaxel followed by erlotinib treatment showed nearly additive effects. On the other hand, erlotinib followed by docetaxel treatment showed remarkable antagonistic interactions. Second, we examined the effect of combinations on the in vitro apoptosis induction. Erlotinib followed by docetaxel treatment reduced apoptosis induction compared with docetaxel alone; in contrast, docetaxel followed by erlotinib treatment had no inhibitory effects on docetaxel-induced apoptosis in any of the cell lines. Finally, an in vivo tumor growth inhibition test was performed using xenograft models. Docetaxel followed by erlotinib administration resulted in significant tumor growth inhibition compared with erlotinib or docetaxel monotherapy in all models. In conclusion, we demonstrated that docetaxel followed by erlotinib therapy was a potentially optimum regimen against NSCLC regardless of the mutation status of EGFR and KRAS.