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谷胱甘肽-S-转移酶P1启动子调控的胞嘧啶脱氨酶和尿嘧啶磷酸核糖转移酶融合基因对卵巢癌顺铂耐药细胞的体外杀伤作用

Killing effect of adenovirus mediated fusion gene cytosine and deaminase uracil phosphoribosyl transferase directed by glutathione S-transferase P1 promoter on cisplatin-resistant ovarian cancer cells in vitro
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摘要 目的 观察谷胱甘肽 S 转移酶P1(GSTP1)启动子调控的胞嘧啶脱氨酶和尿嘧啶磷酸核糖转移酶融合基因 (CD UPP ,即自杀基因 )表达的腺病毒载体 ,对卵巢癌顺铂耐药细胞的体外杀伤作用。方法 采用细菌内同源重组法构建腺病毒载体 ,设立卵巢癌顺铂敏感细胞株A2 780和以其诱导的耐药细胞株A2 780 /DDP ,在体外用重组腺病毒转染两组细胞并联合应用前药 5 氟胞嘧啶 (5 FC) ,观察两组卵巢癌细胞对 5 FC的敏感性。将CD UPP阳性和CK UPP阴性的A2 780 /DDP细胞按不同比例混合后给予 5 FC ,观察 5 FC对混合细胞的杀伤作用。结果 当重组腺病毒滴度为 10 0感染复数(MOI)、5 FC浓度为 2 5 0 μg/ml时 ,对顺铂耐药的A2 780 /DDP细胞的存活率为 (3 6± 1 0 ) % ,对顺铂敏感的A2 780细胞的存活率为 (76 5± 2 8) % ,两者比较 ,差异有显著性 (P <0 0 5 )。此外 ,2 0 %CD UPP阳性A2 780 /DDP细胞 ,即可引起 80 3%的混合细胞死亡 ,CD UPP / 5 FC系统表现出明显的旁观者效应。结论 由腺病毒介导的含有GSTP1调控的CD UPP/ 5 FC系统 ,对卵巢癌顺铂耐药细胞具有特异性杀伤作用 ,为临床上克服卵巢癌化疗耐药 ,提供了一条安全、高效的治疗途径。 Objective To construct an adenoviral vector in which the fusion gene cytosine and uracil phosphoribosyl (UPP) transferase was directed by glutathione S-transferase P1(GSTP1 ) promoter, and to investigate specific killing effect of the suicide gene system on cisplatin-resistant ovarian cancer cells. Methods Recombinant adenovirus was generated through homologous recombination in bacteria. A2780 and A2780/DDP cells were infected with Ad and then received flucytosine (5-FC) administration. The relative survival of these cells was tested. And a bystander effect was observed by mixing gene-transferred and gene-untransferred A2780/DDP cells with 5-FC. Results In vitro, when MOI was 100 and 5-FC was 250 μg/ml, relative survival rate of A2780/DDP cells was only (3.6±1.0)%;that of A2780 cells was (76.5±2.8)%. Significant bystander effect was caused by CD-UPP gene and 20% gene-transferred A2780/DDP cells induced 80.3 % of total cells to death. Conclusion Recombinant adenovirus carrying CD-UPP gene driven by GSTP1 promoter has a specific killing effect on cisplatin-resistant ovarian cancer cells.
出处 《中华妇产科杂志》 CAS CSCD 北大核心 2004年第7期478-481,i004,共5页 Chinese Journal of Obstetrics and Gynecology
基金 国家自然科学基金资助项目 (3 0 0 70 786)
关键词 谷胱甘肽-S-转移酶 P1启动子 胞嘧啶脱氨酶 尿嘧啶磷酸核糖 转移酶 融合基因 卵巢癌 顺铂 耐药细胞 体外杀伤作用 Adenoviridae Glutathione transferase Promoter regions (genetics) Genes transgenic suicide Ovarian neoplasms Cisplatin
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