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首页> 外文期刊>Gene Therapy and Molecular Biology >Efficacy of antiherpetic drugs in combinedgene/chemotherapy of cancer is not affected by aspecific nuclear or cytoplasmic compartmentation ofherpes thymidine kinases
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Efficacy of antiherpetic drugs in combinedgene/chemotherapy of cancer is not affected by aspecific nuclear or cytoplasmic compartmentation ofherpes thymidine kinases

机译：抗疱疹药物在癌症的联合基因/化学疗法中的功效不受疱疹胸苷激酶的特异性核或细胞质区分开的影响

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Introduction of the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) gene in tumor cells, followed by treatment of the transfected tumor cells with an antiherpes drug has shown promise in the treatment of solid tumors. We have recently shown that the HSV-1 TK fused to green fluorescent protein (GFP) was localized almost exclusively in the nuclei of HSV-1 TK-GFP fusion gene-transfected human osteosarcoma cells, due to the presence of a nuclear localization signal (NLS) at the N-terminus of the HSV-1 TK. A deletion mutant, lacking the N-terminal 34 amino acids [ (AA1-34)HSV-1 TK-GFP], was distributed throughout the cytoplasm and nucleus of transfected tumor cells. In addition, varicella-zoster virus (VZV) TK-GFP, which lacks the NLS and which is uniformly distributed in the nucleus and cytoplasm of the VZV TK-GFP gene- transfected tumor cells, could be specifically targeted to the nucleus by ligating the HSV-1 TK nuclear localization signal to the VZV TK-GFP sequence. Two pairs of osteosarcoma cell lines stably expressing HSV-1 TK-GFP or VZV TK-GFP either in the nucleus or throughout the cell were established and compared for their sensitivity to the cytostatic effects of a variety of antiherpetic nucleoside analogues. In addition, the efficacy of nucleoside analogues in contributing to the bystander effect (i.e., the killing of non-transfected tumor cells by neighbouring TK gene- transfected cells after gap junctional transfer of phosphorylated nucleoside metabolites), was evaluated using the HSV-1 TK-GFP and (AA1-34)HSV-1 TK-GFP gene constructs. From our experiments it is inferred that there is no difference in cytostatic activity of the antiherpetic??123Degrève et al: Antiherpetic drugs in combined gene/chemotherapy of cancernucleoside analogues against TK gene-transfected cells, whether the TK activity is solely localized in the nucleus or spread over the nucleus and cytosol. Also, the bystander killing effect of the antiviral compounds was independent of the nature of the intracellular compartment in which the HSV-1 TK-GFP fusion protein was expressed.
机译：在肿瘤细胞中引入单纯疱疹病毒1型（HSV-1）胸苷激酶（TK）基因，然后用抗疱疹药物治疗转染的肿瘤细胞在实体瘤治疗中显示出了希望。我们最近显示，由于存在核定位信号，与绿色荧光蛋白（GFP）融合的HSV-1 TK几乎完全位于HSV-1 TK-GFP融合基因转染的人骨肉瘤细胞核中。 HSV-1 TK的N末端）。缺失N末端34个氨基酸[（AA1-34）HSV-1 TK-GFP]的缺失突变体分布在整个转染的肿瘤细胞的细胞质和细胞核中。另外，可以通过连接水痘带状疱疹病毒（VZV）TK-GFP，该水痘带状疱疹病毒（VZV）TK-GFP缺乏NLS，并且均匀分布在转染了VZV TK-GFP基因的肿瘤细胞的细胞核和细胞质中。 HSV-1 TK核定位信号传递给VZV TK-GFP序列。建立了两对在细胞核中或整个细胞中稳定表达HSV-1 TK-GFP或VZV TK-GFP的骨肉瘤细胞系，并比较了它们对多种抗疱疹性核苷类似物抑制细胞生长作用的敏感性。此外，使用HSV-1 TK评估了核苷类似物对旁观者效应（即在磷酸化核苷代谢物之间间隙连接转移后被相邻TK基因转染的细胞杀死未转染的肿瘤细胞的杀伤力）的功效。 -GFP和（AA1-34）HSV-1 TK-GFP基因构建体。从我们的实验中可以推断出抗疱疹药??123Degrève等人的细胞抑制活性没有差异：TK活性是否仅局限在细胞核中，抗疱疹药在针对TK基因转染细胞的癌核苷类似物的联合基因/化学疗法中或扩散到细胞核和细胞质。而且，抗病毒化合物的旁观者杀伤作用与表达HSV-1 TK-GFP融合蛋白的细胞内区室的性质无关。

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