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首页> 外文期刊>Molecular Cancer >Evaluation of p21 promoter for interleukin 12 radiation induced transcriptional targeting in a mouse tumor model
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Evaluation of p21 promoter for interleukin 12 radiation induced transcriptional targeting in a mouse tumor model

机译：小鼠肿瘤模型中p21启动子对白介素12辐射诱导的转录靶向的评估

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Background Radiation induced transcriptional targeting is a gene therapy approach that takes advantage of the targeting abilities of radiotherapy by using radio inducible promoters to spatially and temporally limit the transgene expression. Cyclin dependent kinase inhibitor 1 (CDKN1A), also known as p21, is a crucial regulator of the cell cycle, mediating G1 phase arrest in response to a variety of stress stimuli, including DNA damaging agents like irradiation. The aim of the study was to evaluate the suitability of the p21 promoter for radiation induced transcriptional targeting with the objective to test the therapeutic effectiveness of the combined radio-gene therapy with p21 promoter driven therapeutic gene interleukin 12. Methods To test the inducibility of the p21 promoter, three reporter gene experimental models with green fluorescent protein (GFP) under the control of p21 promoter were established by gene electrotransfer of plasmid DNA: stably transfected cells, stably transfected tumors, and transiently transfected muscles. Induction of reporter gene expression after irradiation was determined using a fluorescence microplate reader in vitro and by non-invasive fluorescence imaging using fluorescence stereomicroscope in vivo . The antitumor effect of the plasmid encoding the p21 promoter driven interleukin 12 after radio-gene therapy was determined by tumor growth delay assay and by quantification of intratumoral and serum levels of interleukin 12 protein and intratumoral concentrations of interleukin 12 mRNA . Results Using the reporter gene experimental models, p21 promoter was proven to be inducible with radiation, the induction was not dose dependent, and it could be re-induced. Furthermore radio-gene therapy with interleukin 12 under control of the p21 promoter had a good antitumor therapeutic effect with the statistically relevant tumor growth delay, which was comparable to that of the same therapy using a constitutive promoter. Conclusions In this study p21 promoter was proven to be a suitable candidate for radiation induced transcriptional targeting. As a proof of principle the therapeutic value was demonstrated with the radio-inducible interleukin 12 plasmid providing a synergistic antitumor effect to radiotherapy alone, which makes this approach feasible for the combined treatment with radiotherapy.
机译：背景技术辐射诱导的转录靶向是一种基因治疗方法，其通过使用放射性诱导型启动子在空间和时间上限制转基因表达来利用放射疗法的靶向能力。细胞周期蛋白依赖性激酶抑制剂1（CDKN1A），也称为p21，是细胞周期的关键调节剂，可响应各种应激刺激（包括DNA损伤剂，如辐射）介导G1期阻滞。这项研究的目的是评估p21启动子对辐射诱导的转录靶向的适用性，以测试结合p21启动子驱动的治疗基因白介素12的放射基因疗法的治疗效果。 p21启动子是通过质粒DNA的基因电转移建立的三个在p21启动子控制下具有绿色荧光蛋白（GFP）的报告基因实验模型：稳定转染的细胞，稳定转染的肿瘤和瞬时转染的肌肉。在体外使用荧光酶标仪和在体内使用荧光立体显微镜通过无创荧光成像确定诱导后报告基因表达的诱导。通过肿瘤生长延迟测定，定量肿瘤内和血清白细胞介素12蛋白水平以及肿瘤内白细胞介素12 mRNA浓度来确定放射基因治疗后编码p21启动子驱动的白介素12质粒的抗肿瘤作用。结果利用报告基因实验模型，证实p21启动子可以被辐射诱导，诱导作用与剂量无关，并且可以被重新诱导。此外，在p21启动子的控制下用白介素12进行的放射基因治疗具有良好的抗肿瘤治疗效果，并且具有统计学上相关的肿瘤生长延迟，这与使用组成型启动子的相同疗法相当。结论在本研究中，p21启动子被证明是辐射诱导的转录靶向的合适候选物。作为原理的证明，放射诱导型白介素12质粒对单独的放射疗法提供了协同的抗肿瘤作用，证明了治疗价值，这使得该方法对于放射疗法的联合治疗是可行的。

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