联合胞嘧啶脱胺酶与尿嘧啶磷酸核糖转移酶基因治疗小鼠胃癌

Combined cytosine deaminase and uracil phosphoribosyl transferase gene therapy for gastric cancer xenografts in nude mice

目的探讨联合应用尿嘧啶磷酸核糖转移酶(UPRT)基因对胞嘧啶脱胺酶(CD)/氟胞嘧啶(5-FC)前药转换酶系统抗瘤作用的增强效应。方法将携带UPRT基因和CD基因的逆转录病毒载体通过PA317细胞包装成完整的病毒颗粒并浓缩和纯化。建立615小鼠胃癌皮下移植瘤模型,瘤内反复多次注射携带UPRT和CD基因的逆转录病毒,同时腹腔内给予5-FC,观察抑瘤效果。结果逆转录病毒介导CD基因瘤内原位转导,同时联合应用5-FC进行治疗,结果发现,在肿瘤接种后第12天,对照组肿瘤体积为(2.367±0.371)cm3,而CD/5-FC治疗组肿瘤体积大小为(0.704±0.358)cm3,肿瘤生长明显受抑(P<0.0005)。联合转导UPRT基因后,于肿瘤接种后第16天,肿瘤体积为(0.731±0.255)cm3,而单独应用CD基因治疗组肿瘤体积为(1.455±0.370)cm3,从而证实联合转导UPRT基因可进一步增强CD/5-FC自杀基因系统的抑瘤作用(P<0.001)。结论联合转导UPRT基因,可显著增强CD/5-FC自杀基因系统的抗瘤效应。

Objective To investigate the enhanced antitumor effect of cytosine deaminase/5 fluorocytosine enzyme prodrug system (CD/5 FC) combined with uracil phosphoribosyl transferase(UPRT) gene therapy on gastric cancer xenografts in 615 mice. Methods Recombinant retrovirus carrying CD and UPRT gene was packaged by PA317 cells and further concentrated and purified, and repeatedly injected intratumorally, which was followed by administration of 5 FC (500 mg/kg) intraperitoneally. Results Retrovirus mediated transduction of CD gene in situ followed by administration of 5 FC intraperitoneally inhibited tumor growth significantly. The mean tumor volume in the group of CD gene therapy was (0 704±0 358)cm3, smaller than (2 367±0 371) cm3 in the control group at day 12 after tumor cells inoculation (P< 0 0005). As observed at day 16, combined transduction of UPRT with CD gene enhanced the antitumor effect more significantly with a mean volume of (0 731±0 255)cm3, smaller than (1 455±0 370)cm3 in the group of CD/5 FC system alone (P< 0 001). Conclusion Repeated injections of retroviruses carrying CD gene intratumorally followed by administration of the prodrug 5 FC is a useful modality for the treatment of gastric carcinoma, and combined transduction of the UPRT gene can further enhance the antitumor effect of CD/5 FC system.