Pharmacokinetics of combined gene therapy expressing constitutive human GM-CSF and hyperthermia-regulated human IL-12.
Pharmacokinetics of combined gene therapy expressing constitutive human GM-CSF and hyperthermia-regulated human IL-12.
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DOI：
10.1186/1756-9966-32-5
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发表时间：
2013-01-26
期刊：
影响因子：
--
通讯作者：
Huang Q
中科院分区：
文献类型：
--
作者：
Wei F;Wang H;Zhang J;Chen X;Li C;Huang Q
一种表达白细胞介素 (IL)-12 和粒细胞巨噬细胞集落刺激因子 (GM-CSF) 的腺病毒已被证明对治疗多种肿瘤非常有效，但会引起严重的正常组织毒性。本研究通过将人GM-CSF基因置于CMV-IE启动子控制下，将人IL-12基因置于热休克蛋白70B基因启动子控制下，构建了一种新型腺病毒载体。在单轮或多轮热疗时，在体外和体内分析了病毒感染的肿瘤细胞中 hGM-CSF 和 hIL-12 的表达。我们观察到病毒感染后单轮热疗后人 GM-CSF 的组成型高表达和人 IL-12 的热诱导表达。热诱导的 hIL-12 表达呈现脉冲状模式，在 24 小时达到峰值，随后在热应激后 48 小时下降。重复热处理比一次性热处理更能有效诱导 hIL-12 表达。有趣的是，我们还观察到在测试的肿瘤细胞中热应激可以刺激 hGM-CSF 的组成型表达。我们的研究提供了一种新的联合基因治疗策略，允许非毒性基因（如 GM-CSF）的组成型表达和毒性基因（如 IL-12）的热诱导表达。此外，我们的研究还表明，热疗可以以暂时的、特殊的方式触发基因表达。
An adenovirus that expresses both interleukin (IL)-12 and granulocyte-macrophage colony-stimulating-factor (GM-CSF) has been proven to be very effective in treating several tumors, but causes serious normal tissue toxicities. In this study, a novel adenoviral vector was constructed by placing the human GM-CSF gene under the control of the CMV-IE promoter and human IL-12 gene under the control of heat shock protein 70B gene promoter. Both hGM-CSF and hIL-12 expressions in virus-infected tumor cells were analyzed in vitro and in vivo when underlying single or multiple rounds of hyperthermia. We observed constitutive high expression of human GM-CSF and heat-induced expression of human IL-12 after a single round of hyperthermia post viral infection. The heat-induced hIL-12 expression exhibited a pulse-like pattern with a peak at 24 hrs followed by a decline 48 hrs post heat stress. Repeated heat treatment was more effective in inducing hIL-12 expression than a one-time heat treatment. Interestedly, we also observed that constitutive expression of hGM-CSF could be stimulated by heat stress in tested tumor cells. Our study provided a novel strategy for combined gene therapy that allows constitutive expression of a non-toxic gene such as GM-CSF and heat-induced expression of a toxic gene such as IL-12. In addition, our study also showed that hyperthermia can be used to trigger gene expression in temporal and special manner.
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影响因子：
3.8
作者：
GEELEN, JLMC;BOOM, R;VANDERNOORDAA, J
通讯作者：
VANDERNOORDAA, J
影响因子：
4.7
作者：
Pshenichkin, Sergey;Surin, Alexander;Wroblewski, Jarda T.
通讯作者：
Wroblewski, Jarda T.
影响因子：
5.1
作者：
Choi, K-J;Zhang, S-N;Yun, C-O
通讯作者：
Yun, C-O
影响因子：
2.6
作者：
Kobelt, Dennis;Aumann, Jutta;Walther, Wolfgang
通讯作者：
Walther, Wolfgang
DOI：
10.1073/pnas.82.15.4949
发表时间：
1985-01-01
影响因子：
11.1
作者：
VOELLMY, R;AHMED, A;RUNGGER, D
通讯作者：
RUNGGER, D