Tanaka T, Kanai F, Okabe S, Yoshida Y, Wakimoto H, Hamada H, Shiratori Y, Lan K, Ishitobi M, Omata M
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Cancer Res. 1996 Mar 15;56(6):1341-5.
We analyzed the ability of a recombinant replication-defective adenovirus vector with the carcinoembryonic antigen (CEA) promotor to transfer the thymidine kinase gene of herpes simplex virus (HSVtk) into gastric cancer cells to confer sensitivity to ganciclovir (GCV). CEA-producing gastric cancer cell lines (MKN28 and MKN45), a CEA-nonproducing gastric cancer cell line (MKN1), and a human uterine cervical cancer cell line (HeLa) were infected with a recombinant adenovirus carrying lacZ reporter gene coupled to the CEA promoter (AdCEAlacZ). The efficiency of AdCEAlacZ-mediated gene transfer was correlated with the amount of CEA produced by each cell line. Furthermore, the 50% growth inhibitory concentrations (IC50) of GCV were 21 and 5.8 microm for MKN28 and MKN45, respectively, when infected with a recombinant adenovirus carrying the HSVtk gene coupled to the CEA promoter (AdCEAtk). However, MKN1 and HeLa cells infected with AdCEAtk remained resistant to GCV (IC50 > 300 microm of GCV). In addition, a bystander killing effect was demonstrated against MKN45 cells when only 20% of AdCEAtk-infected cells were mixed with uninfected cells. These data indicate the potential for targeted gene therapy using the cell type-specific promotor of the CEA gene against gastric cancers that produce CEA.
我们分析了一种带有癌胚抗原（CEA）启动子的重组复制缺陷型腺病毒载体将单纯疱疹病毒胸苷激酶基因（HSVtk）导入胃癌细胞以使其对更昔洛韦（GCV）敏感的能力。用携带与CEA启动子偶联的lacZ报告基因的重组腺病毒（AdCEAlacZ）感染产生CEA的胃癌细胞系（MKN28和MKN45）、不产生CEA的胃癌细胞系（MKN1）以及人子宫颈癌细胞系（HeLa）。AdCEAlacZ介导的基因转移效率与每个细胞系产生的CEA量相关。此外，当用携带与CEA启动子偶联的HSVtk基因的重组腺病毒（AdCEAtk）感染时，MKN28和MKN45对GCV的50%生长抑制浓度（IC50）分别为21和5.8微摩尔。然而，用AdCEAtk感染的MKN1和HeLa细胞对GCV仍有抗性（GCV的IC50>300微摩尔）。另外，当仅将20%的AdCEAtk感染细胞与未感染细胞混合时，对MKN45细胞显示出旁观者杀伤效应。这些数据表明利用CEA基因的细胞类型特异性启动子针对产生CEA的胃癌进行靶向基因治疗的潜力。
