Robe P A, Princen F, Martin D, Malgrange B, Stevenaert A, Moonen G, Gielen J, Merville M, Bours V
Department of Neurosurgery, University of Liège, Liège, Belgium.
Biochem Pharmacol. 2000 Jul 15;60(2):241-9. doi: 10.1016/s0006-2952(00)00315-4.
The herpes simplex virus type 1 thymidine kinase (HSV1-tk) suicide gene/ganciclovir system was first applied to the treatment of glioblastoma tumors, but was hampered by the low gene transfection yield. Fortunately, the gap junction-dependent diffusion of phosphorylated ganciclovir metabolites from transfected cells to their neighbors proved to enhance the overall benefit of this strategy. However, as tumor cells are often gap junction-deficient, we sought to restore this property pharmacologically and hence to improve the efficacy of the treatment. We demonstrated that this approach was feasible in glioblastoma cells using dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) (100 microM) as a pharmacological inducer of gap junctions. alpha-Glycyrrhetinic acid (25 microM), on the other hand, strongly inhibited both gap junction-mediated intercellular communication and the bystander effect, thus confirming the role of gap junctions in HSV-tk-mediated bystander killing. Using cytosine arabinoside as a growth inhibitor, we underlined the role of tumor cell proliferation in the sensitivity of HSV-tk-transfected cells to ganciclovir and demonstrated its correlation with the importance of the bystander effect.
单纯疱疹病毒1型胸苷激酶（HSV1 - tk）自杀基因/更昔洛韦系统最初应用于胶质母细胞瘤的治疗，但因基因转染率低而受到阻碍。幸运的是，磷酸化更昔洛韦代谢产物从转染细胞向其相邻细胞的间隙连接依赖性扩散证明可增强该策略的整体益处。然而，由于肿瘤细胞通常缺乏间隙连接，我们试图通过药理学方法恢复这一特性，从而提高治疗效果。我们证明，使用二丁酰腺苷3'，5'-环磷酸腺苷（cAMP）（100微摩尔）作为间隙连接的药理学诱导剂，这种方法在胶质母细胞瘤细胞中是可行的。另一方面，α-甘草次酸（25微摩尔）强烈抑制间隙连接介导的细胞间通讯和旁观者效应，从而证实了间隙连接在HSV - tk介导的旁观者杀伤中的作用。使用阿糖胞苷作为生长抑制剂，我们强调了肿瘤细胞增殖在HSV - tk转染细胞对更昔洛韦敏感性中的作用，并证明了其与旁观者效应重要性的相关性。
