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Chengdu, China

Ding M.,Chongqing Medical University | Li R.,Chongqing Medical University | He R.,Chongqing Medical University | Wang X.,Chongqing Medical University | And 2 more authors.
Cancer Science | Year: 2015

Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6, heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy. © 2015 Japanese Cancer Association. Source


Ding M.,Chongqing Medical University | Zhang E.,Chongqing Medical University | He R.,Tumor Hospital of Sichuan | Wang X.,Tumor Hospital of Sichuan | And 3 more authors.
Cancer Gene Therapy | Year: 2012

The AND gate functions such that when all inputs are activated the downstream gene will be transcribed and it is off otherwise. To accomplish optimal and targeted gene therapy in solid tumor patients, we have constructed an AND gate genetic circuit and investigated whether it could be activated by low-dose radiation in vitro and in vivo. The enhancement green fluorescent protein (EGFP) expression in different tumor cells transfected with control vector plxsn-EGFP confirmed that 2 Gy of radiation and 1% O 2 for 3 h could activate our AND gate. Besides, the obvious different levels of EGFP expression between 2 and 6 Gy of radiation demonstrated that the AND gate could be regulated by radiation doses. Additionally, through EGFP expression and the codistribution of p53 and HIF-1α in xenografts, we illustrated the targeted activation property of the AND gate and real-time monitoring to hypoxic districts in vivo. Moreover, significant growth inhibition and cell cycle arrest in vitro and apoptosis-inducing effects in vitro and in vivo proved that the AND gate induced ideal antitumor effects. In conclusion, the radiation dose-regulated AND gate genetic circuit could not only effectively monitor the therapeutic process in real-time but also induce ideal antitumor efficacy, and can be further exploited for personal therapy in clinical tumor patients. © 2012 Nature America, Inc. All rights reserved. Source

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