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

• Published in: Journal of experimental & clinical cancer research Vol. 32; no. 1; p. 5
• Main Authors: Wei, Fang, Wang, Huiping, Zhang, Jufeng, Chen, Xiafang, Li, Chuanyuan, Huang, Qian
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26.01.2013; BioMed Central; BMC
• Subjects: Adenoviridae - genetics; Adenovirus; Adenoviruses; Analysis; Animals; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - therapy; Carcinoma, Non-Small-Cell Lung - virology; Cell culture; Cell Culture Techniques; Cell Line, Tumor; Cytotoxicity; Experiments; Fever; Gene expression; Gene therapy; Genes; Genetic research; Genetic Therapy - methods; GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacokinetics; Health aspects; Heat shock proteins; Hsp70; Humans; Hyperthermia; Hyperthermia, Induced - methods; IL-12; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Interleukin-12 - pharmacokinetics; Interleukins; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - therapy; Liver Neoplasms - virology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - therapy; Lung Neoplasms - virology; Mice; Mice, Inbred BALB C; Mice, Nude; Physiological aspects; Studies; Toxicity; Tumors; Virus diseases; Xenograft Model Antitumor Assays
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/1756-9966-32-5

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.