不同化疗药物对结肠癌细胞获得性TRAIL基因耐药的逆转作用  

Effects of different chemotherapeutic agents on reversing the acquired resistance to TRAIL gene in DLD1 colon cancer cells

作　　者：朱洪波[1] 卓文莹[1] 何超[1] 黄学锋[1] 朱玉萍[1] 王达[1] 方炳良[2] 

机构地区：[1]浙江大学医学院附属邵逸夫医院肛肠外科临床医学研究所,浙江杭州310016 [2]美国M.D.Anderson癌症中心

出　　处：《中国病理生理杂志》2007年第2期231-235,共5页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.30271467)

摘　　要：目的:探讨不同化疗药物对结肠癌DLD1细胞获得性TRAIL基因耐药的逆转作用及其可能的机制。方法:将不同化疗药物联合重组腺病毒载体(Ad)介导的TRAIL基因处理对Ad/gTRAIL耐药的结肠癌DLD1-TRAIL/R细胞,通过MTT法检测治疗后肿瘤细胞的存活率,以评价化疗药物对TRAIL基因耐药的逆转作用;然后进一步在体内评价该逆转策略的有效性;接着通过Western免疫印迹等方法探讨逆转耐药的可能机制。结果:在体外检测了5-氟脲嘧啶、丝裂霉素、阿霉素、氟脲苷、依立替康以及顺铂6种化疗药物对DLD1-TRAIL/R细胞TRAIL基因耐药的逆转作用,结果发现只有5-氟脲嘧啶和丝裂霉素能够使DLD1-TRAIL/R细胞对Ad/gTRAIL重新敏感。进一步的结果表明联合5-氟脲嘧啶和Ad/gTRAIL能在体内有效地抑制DLD1-TRAIL/R细胞来源的肿瘤生长,且该抑制作用明显强于其它对照组。结论:联合使用Ad/gTRAIL和5-氟脲嘧啶或丝裂霉素能在体内外有效地逆转DLD1-TRAIL/R细胞对TRAIL基因的获得性耐药,其中丝裂霉素的逆转作用可能与其诱导的Bax过度表达有关。AIM： To evaluate effects of different chemotherapeutic agents on reversing the acquired resistance to TRAIL gene and clarify the involved mechanisms in DLD1 - TRAIL/R colon cancer cells. METHODS ： Human colon cancer cell line DLD1 - TRAIL/R cells that were resistant to TRAIL - expressing adenovector （Ad/gTRAIL） were treated with Ad/ gTRAIL combined with different chemotherapeutic agents. Then, the cell viability was measured by MTT method, and apoptotic signaling conditions, including activation of caspase - 3 and caspase - 8, expression of Bax and Bcl - XL, were meas- ured by Western blotting analysis. RESULTS： In vitro data showed that several chemotherapeutic agents, including 5 - fluorouracil （5 -FU） and mitomycin c （MMC）, overcome the acquired resistance to TRAIL gene in DLD1 -TRAIL/R colon cancer cells. The combination of Ad/gTRAIL and 5 - FU effectively suppressed tumor growth in vivo in subcutaneous tumors established from DLD1 - TRAIL/R cells. Further data showed that treatment with the combination of Ad/gTRAIL and 5 - FU or MMC led to enhance the activation of caspase - 3. Moreover, MMC but not 5 - FU induced overexpression of Bax gene that was sufficient to overcome the resistance to TRAIL gene in DLD1 -TRAIL/R cells. CONCLUSION： Chemotherapeutic agents, such as 5 -FU and MMC, overcome the acquired resistance to TRAIL gene in DLD1 -TRAIL/R cells. The candidate mechanisms for MMC but not 5 - FU to overcome this resistance might involve the induction of over - expressed Bax protein in DLD1 -TRAIL/R cells.

关 键 词：基因 TRAIL 结肠肿瘤 药物疗法 

分 类 号：R363[医药卫生—病理学]