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Pharmacokinetics of combined gene therapy expressing constitutive human GM-CSF and hyperthermia-regulated human IL-12

Fang Wei1, Huiping Wang1, Jufeng Zhang1, Xiafang Chen1, Chuanyuan Li2* and Qian Huang1*

Author Affiliations

1 Experimental Research Center, First People’s Hospital, School of Medicine, Shanghai Jiaotong University, 85 Wujin Road, Shanghai, 200080, China

2 Department of Dermatology, Duke University Medical Center, Durham, NC, 27710, USA

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Journal of Experimental & Clinical Cancer Research 2013, 32:5  doi:10.1186/1756-9966-32-5

Published: 26 January 2013

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords:
GM-CSF; IL-12; Adenovirus; Hsp70; Hyperthermia