Escherichia coli B nitroreductase (NR) has been expressed stably in MDA-MB-361 human breast adenocarcinoma cells either as the wild-type protein (wtNR), which is distributed evenly between the cytoplasmic and nuclear compartments, or targeted to the mitochondrion (mtNR). Whereas bacterial NR is active as a dimer, a proportion of wtNR is monomeric. In contrast, mtNR is mostly dimeric, suggesting that it adopts a more stable, native conformation. Despite this, when tested in gene-directed enzyme prodrug therapy cell cytotoxicity studies, cells expressing wtNR or mtNR had similar sensitivity to the prodrug CB1954 and mounted similar bystander killing effects. Furthermore, when short prodrug exposures were given, wtNR was more efficient at killing cells than mtNR. These data demonstrate that the site of enzyme expression and prodrug activation is an important variable that requires consideration in suicide gene therapy approaches.

译文

大肠杆菌B硝基还原酶 (NR) 已在MDA-MB-361人乳腺腺癌细胞中稳定表达为野生型蛋白 (wtNR),该蛋白均匀分布在细胞质和核区室之间,或靶向线粒体 (mtNR)。细菌NR作为二聚体具有活性,而wtNR的一部分是单体的。相反,mtNR主要是二聚体,表明它采用了更稳定的天然构象。尽管如此,当在基因导向酶前药疗法细胞细胞毒性研究中进行测试时,表达wtNR或mtNR的细胞具有与前药CB1954相似的敏感性,并具有相似的旁观者杀伤作用。此外,当给予短时间的前药暴露时,wtNR在杀死细胞方面比mtNR更有效。这些数据表明,酶表达和前药激活的位点是自杀基因治疗方法中需要考虑的重要变量。

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