肺腺癌组织特异性自杀基因治疗实验研究

目的 探讨肺腺癌组织特异性自杀基因治疗的安全性及有效性。方法 采用病毒感染法，将癌胚抗原(CEA)基因启动子所驱动的CD基因的组织特异性逆转录病毒载体(G1CEACDNa)，导入分泌CEA的肺腺癌细胞系A549细胞．研究裸鼠体内抑瘤效果；应用重组逆转录病毒裸鼠体内治疗A549肿瘤，观察G1CEACDNa／5-氟胞嘧啶(5-FC)对A549细胞致瘤裸鼠的治疗作用及毒副反应。结果 (1)将转基因的A549细胞和未转基因的A549细胞接种至裸鼠皮下．两者成瘤性无明显差异；(2)在转基因细胞致瘤裸鼠实验中，5-FC对转CEA启动子调控自杀基因的肿瘤生长具有明显的抑制作用；(3)将G1CEACDNa重组逆转录病毒上清直接注射到裸鼠成瘤部位．然后腹腔内注射5-FC同样获得明显的抑瘤效果；(4)与直接注射5-FU相比，组织特异性自杀基因治疗对骨髓的抑制明显降低。结论 组织特异性自杀基因治疗可能成为肿瘤治疗个体化的重要方法之一。

Experimental study of tissue-specific suicide gene therapy for lung adenocarcinoma

Objective To study the effect and safety of tissue specific gene therapy of suicide gene for lung adenocarcinoma. Methods Retroviral vector of G 1CEACDNa contained a carcinoembryonic antigen (CEA) promoter regulated cytosine deaminase expression cassete (CEA/CD). By means of infection of virus, tissue specific expressing vectors and non specific expressing vectors were transfected into A549 cell, which was CEA producing lung adenocarcinoma cell line and then xenografted in nude mice, and the anti tumor effect was evaluated. Then the retrovirus was injected directly into the tumor mass on nude mice, and the sensitivity of the xenograft to G 1CEACDNa/5 fluorocytosine (5 FC) and the side effects were observed. Results (1) After transfected and untransfected A549 cells were implanted into nude mice, there was no difference in tumor formation among all the groups. (2) After 5 FC administration, the tumor transfected with tissue specific gene displayed a higher sensitivity to the drug than those treated with non specific in vitro gene therapy. (3) The tumor bearing nude mice were randomized in a blind manner based on comparable size to receive the supernatant of recombinant retrovirus G 1CEACDNa followed by 5 FC, and significant growth suppression could be observed. (4) Comparing to the group with injection of 5 fluorouracil (5 FU) alone, tissue specific suicide gene therapy showed lower suppression to bone marrow. Conclusion The results suggest that tissue specific suicide gene therapy may play an important role in individual treatment of lung cancer.