Rosolen A, Frascella E, di Francesco C, Todesco A, Petrone M, Mehtali M, Zacchello F, Zanesco L, Scarpa M
Department of Pediatrics, University of Padua, Italy.
Gene Ther. 1998 Jan;5(1):113-20. doi: 10.1038/sj.gt.3300559.
Herpes simplex virus thymidine kinase gene (HSVtk) transfer together with treatment with the prodrug ganciclovir (GCV) represents the most commonly used suicide gene approach for the gene therapy of human central nervous system malignancies. Despite encouraging results reported in clinical trials conducted in adults, very little is known about the feasibility of this approach for the treatment of CNS tumors of childhood. We studied the effects of the HSVtk/GCV system on human medulloblastoma cells in vitro and in vivo. The transfer of tk gene to medulloblastoma cells was capable of mediating cell suicide in vitro and in vivo upon treatment with GCV, but the overall effect in vivo appeared to be suboptimal. The relatively low sensitivity of the medulloblastoma cells to viral infection and a limited bystander effect, coupled with a low expression of connexin-43 protein, might partially explain these results. Whether this is a peculiarity of the cell line studied or a general characteristic of medulloblastoma remains to be determined. These findings should be taken into account for the future planning of gene therapy trials for human medulloblastoma.
单纯疱疹病毒胸苷激酶基因（HSVtk）转移并联合使用前药更昔洛韦（GCV）治疗是人类中枢神经系统恶性肿瘤基因治疗中最常用的自杀基因方法。尽管在成人临床试验中报告了令人鼓舞的结果，但对于这种方法治疗儿童中枢神经系统肿瘤的可行性知之甚少。我们在体外和体内研究了HSVtk/GCV系统对人髓母细胞瘤细胞的影响。tk基因转移到髓母细胞瘤细胞后，在用GCV治疗时能够在体外和体内介导细胞自杀，但体内的总体效果似乎并不理想。髓母细胞瘤细胞对病毒感染的相对低敏感性、有限的旁观者效应以及连接蛋白43蛋白的低表达，可能部分解释了这些结果。这是所研究细胞系的特性还是髓母细胞瘤的普遍特征，仍有待确定。在未来人类髓母细胞瘤基因治疗试验的规划中应考虑这些发现。
