上皮-间质转化在人结肠癌细胞系SW480对西妥昔单抗及氟尿嘧啶耐药中的作用

目的探讨人结肠癌细胞系SW480上皮-间质转化现象与其在化疗药物及靶向药物耐药中的作用.方法西妥昔单抗(cetuximab,C225)、5-氟尿嘧啶(5-Fu)以及二者联合处理人结肠癌细胞系SW480,观察细胞形态,免疫荧光化学方法检测处理前后SW480细胞骨架改变以及E-钙粘素(E-cardherin)、波形蛋白(vinmentin)表达差异,Western blot方法检测实验组与对照组SW480细胞E-cardherin、Vinmentin以及多药耐药蛋白(MRP)、P-糖蛋白(P-gp)表达差异;体外药物敏感试验(cell Counting Kit-8,CCK-8比色法)分别检测实验组与对照组SW480细胞存活能力.结果 SW480细胞经C225、5-Fu以及二者联合处理后细胞形态由上皮细胞向间质细胞转化;细胞免疫荧光显示处理前后SW480细胞骨架改变,微丝蛋白排列极性增强,E-cardherin表达下降,Vinmentin表达升高,同时伴随MRP、P-gp表达增高.SW480细胞经C225与5-Fu联合处理较单独应用2个药物细胞存活率明显降低(P<0.05).结论 SW480细胞经单独使用靶向药物或化疗药物以及两者联合应用可诱导细胞发生EMT,且此EMT对肿瘤细胞耐药有影响.     

Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck

Background: Radiation dermatitis occurs to some degree in mostpatients receiving radiotherapy, with or without chemotherapy.Patients with squamous cell carcinoma of the head and neck (SCCHN)who receive radiotherapy in combination with epidermal growthfactor receptor (EGFR) inhibitors, such as cetuximab, may developa characteristic acne-like rash in addition to dermatitis. Design: An advisory board of 11 experienced radiation oncologists,medical oncologists and dermatologists discussed the managementoptions for skin reactions in patients receiving EGFR inhibitorsand radiotherapy for SCCHN. Skin toxicity was categorised accordingto the National Cancer Institute—Common Terminology Criteriafor Adverse Events (version 3) grading. Results: Both general and grade-specific approaches for themanagement of dermatitis in this patient group are presented.It was concluded that where EGFR inhibitor-related acne-likerash and dermatitis coexist within irradiated fields, managementshould be based on the grade of dermatitis: for grade 1 (orno dermatitis), treatment recommendations for EGFR-related acne-likerash outside irradiated fields should be followed; for grades2 and above, treatment recommendations for dermatitis were proposed. Conclusions: This paper presents comprehensive consensus guidelinesfor the treatment of dermatitis in patients with SCCHN receivingEGFR inhibitors in combination with radiotherapy. Key words: cetuximab, EGFR inhibitors, radiation dermatitis, radiotherapy, skin reactions, squamous cell carcinoma of the head and neck Received for publication June 26, 2007. Revision received July 12, 2007. Accepted for publication July 12, 2007.     

西妥昔单抗联合伊立替康治疗晚期胃癌对患者核因子κB、正常上皮细胞特异性1蛋白表达及生存期的影响

目的研究西妥昔单抗联合伊利替康治疗晚期胃癌对患者核因子κB(NF-κB)、正常上皮细胞特异性1(NES1)蛋白表达及生存期的影响。方法将80例晚期胃癌患者根据治疗方法不同分为研究组和对照组各40例,研究组利用西妥昔单抗联合伊立替康治疗,对照组单独利用西妥昔单抗治疗,比较两组患者癌胚抗原(CEA)NF-κB、NES1表达情况、治疗效果、不良反应发生情况和生存情况。结果研究组治疗后有效率为85.00%(34/40),与对照组的70.00%(28/40)比较,差异无统计学意义(P﹥0.05)。治疗前,两组患者CEA、NES1、NF-κB水平比较,差异均无统计学意义(P﹥0.05)。治疗后,研究组患者CEA水平明显低于对照组,NES1、NF-κB水平明显高于对照组,差异均有统计学意义(P﹤0.01)。研究组患者不良反应总发生率为20.00%(8/40),低于对照组的42.50%(17/40),差异有统计学意义(P﹤0.05)。研究组治疗后1年中位生存期为8.26个月(95%CI:6.154~9.985),长于对照组的6.54个月(95%CI:5.112~8.013),差异有统计学意义(P﹤0.05);研究组治疗后复发4例,少于对照组的10例,差异有统计学意义(P﹤0.05)。结论西妥昔单抗联合伊立替康治疗晚期胃癌具有良好的疗效,提高了NF-κB、NES1表达水平,降低了不良反应发生率并延长患者的生存期,对晚期胃癌患者的诊疗有指导意义。     

西妥昔单抗联合调强放疗及TP方案化疗治疗局部晚期鼻咽癌初步研究

[目的]研究西妥昔单抗联合调强放疗及TP方案化疗治疗局部晚期鼻咽癌的近期疗效及不良反应.[方法] 21例局部区域晚期鼻咽癌患者接受调强放射治疗及TP方案同步化疗2个周期,同时接受每周1次的西妥昔单抗治疗.采用CTCAE 3.0记录治疗期间的最大不良反应;观察局部区域控制及远处转移情况.[结果] 21例患者都完成预定调强放射治疗计划,20例(95.2％)患者完成了预定的西妥昔单抗治疗,19例(90.5％)患者完成了2个周期的TP方案化疗.无治疗相关性死亡发生,4级不良反应包括白细胞减少(7例,33.4％),中性粒细胞减少(3例,14.3％),血小板减少(1例,4.8％)及4级唑疮样皮疹(1例,4.8％).口腔及口咽黏膜炎、骨髓抑制、放射性皮炎、呕吐为常见的3级毒性.中位随访13个月,21例患者1年局部控制率、区域控制率及无远处转移生存率为100.0％、100.0％及95.2％.[结论]西妥昔单抗联合调强放疗及TP方案化疗治疗局部晚期鼻咽癌近期疗效令人鼓舞,不良反应可控可逆.     

抗ENO1抗体联合二甲双胍通过靶向肿瘤干细胞逆转人非小细胞肺癌A549细胞对西妥昔单抗的抵抗

目的:探究抗烯醇化酶1 (enolase 1,ENO1)抗体、二甲双胍(metformin,MET)通过靶向肿瘤干细胞对西妥昔单抗(cetuximab,CTX)耐药型非小细胞肺癌A549细胞增殖、迁移、侵袭和干性的影响及其可能的作用机制.方法:10 mmol/L MET联合40μg/ml抗ENO1抗体处理CTX(35 ...     

癌前病变Caspase-3表达下调与胃粘膜癌变的关联

Objective  

Cetuximab is an effective medicine for colorectal cancer bearing wild type Kras. However, few studies of cetuximab on patients with noncolorectal gastrointestinal cancer were available now. The aim of this study was to summarize the efficacy and safety profiles base-on the experiences of 16 patients with noncolorectal gastrointestinal cancer accepted cetuximab-contained regimens treatment.     

C225对不同照射模式CNE-2裸鼠移植瘤Bax、Bcl-2表达的影响研究

目的研究西妥昔单抗(C225)对不同照射模式人鼻咽低分化鳞癌细胞(CNE-2)裸鼠移植瘤细胞凋亡相关基因Bax、Bcl-2表达的影响。方法成功构建48只CNE-2裸鼠移植瘤模型,待成瘤后随机分为空白对照组、急速照射组、模拟IMRT组、C225组、急速照射+C225组、模拟IMRT+C225组,运用RT-PCR法检测Bax、Bcl-2的转录水平。结果 Bax转录水平:空白对照组、急速照射组、模拟IMRT组、C225组、急速+C225组和模拟IM-RT+C225组转录水平分别为0.452、0.662、0.558、0.542、0.621、0.555,放疗后Bax表达上调,急速照射组表达高于模拟IMRT组(P=0.005);使用C225后Bax表达上调(P=0.015);急速与急速+C225组、模拟IMRT组与模拟IMRT+C225组差异均无统计学意义(P>0.05)。Bcl-2转录水平:空白对照组、急速照射组、模拟IMRT组、C225组、急速+C225组和模拟IMRT+C225组转录水平分别为0.629、0.685、0.654、0.625、0.658、0.648,各组差异均无统计学意义(P>0.05)。结论模拟IMRT照射时间延长,影响Bax的表达;C225可能具有一定促凋亡作用;放疗联合C225同单独使用放疗相比Bax表达无明显差异;照射及应用C225后Bcl-2表达的相对稳定,不受照射方式及C225的影响。     

Modulation of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines

Background and purpose:

Oxaliplatin is the first platinum-based compound effective in the treatment of colorectal cancer. Oxaliplatin combined with cetuximab for metastatic colorectal cancer is under evaluation. The preliminary results seem controversial, particularly for the use of cetuximab in K-Ras mutated patients. K-Ras mutation is known to affect redox homeostasis. Here we evaluated how the efficacy of oxaliplatin alone or combined with cetuximab varied according to the Ras mutation and redox status in a panel of colorectal tumour cell lines.

Experimental approach:

Viability was evaluated by methylthiazoletetrazolium assay, reactive oxygen species production by DCFDA and lucigenin on HT29-D4, Caco-2, SW480 and SW620 cell lines.

Key results:

Combination of oxaliplatin and cetuximab was less cytotoxic than oxaliplatin alone in colorectal cells harbouring wild-type Ras and membrane expression of receptors for epidermal growth factor receptor (EGFR), such as HT29-D4 and Caco-2 cells. In contrast, cetuximab did not affect oxaliplatin efficiency in cells harbouring K-Ras^V12 mutation, irrespective of membrane EGFR expression (SW620 and SW480 cells). Transfection of HT29-D4 with K-Ras^V12 decreased oxaliplatin IC₅₀ and impaired cetuximab sensitivity, without affecting expression of membrane EGFR compared with HT29-D4 control. Oxaliplatin efficacy relies on endogenous production of H₂O₂. Cetuximab inhibits H₂O₂ production inhibiting the EGFR/Nox1 NADPH oxidase pathway. Oxaliplatin efficacy was impaired by short hairpin RNA for Nox1 and by catalase (H₂O₂ scavenger).

Conclusions and implications:

Cetuximab limited oxaliplatin efficiency by affecting the redox status of cancer cells through Nox1. Such combined therapy might be improved by controlling H₂O₂ elimination.