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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wei, F; Wang, H; Zhang, J; Chen, X; Li, C; Huang, Q

Published Date

  • January 26, 2013

Published In

Volume / Issue

  • 32 /

Start / End Page

  • 5 -

PubMed ID

  • 23352035

Pubmed Central ID

  • 23352035

Electronic International Standard Serial Number (EISSN)

  • 1756-9966

Digital Object Identifier (DOI)

  • 10.1186/1756-9966-32-5

Language

  • eng

Conference Location

  • England