Anti-angiogenic effects of interleukin-12 delivered by a novel hyperthermia induced gene construct

Farzan Siddiqui, E. J. Ehrhart, Brad Charles, Laura Chubb, Chuan Yuan Li, Xiuwu Zhang, Susan M. Larue, Paul R. Avery, Mark W. Dewhirst, Robert L. Ullrich

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21 Scopus citations

Abstract

Purpose: Interleukin-12 (IL-12) is a pro-inflammatory cytokine possessing anti-cancer and anti-angiogenic properties. This study quantitatively assessed the anti-angiogenic effect of IL-12 delivered using an adenoviral vector with murine IL-12 placed under control of a heat shock promoter. This approach limits systemic toxicity by restricting IL-12 delivery locally to the tumour. The kinetics of the downstream cytokines interferon-γ (IFN-γ) and interferon inducible protein-10 (IP-10) and other molecules affecting angiogenesis, vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAI-1) were also studied. Materials and methods: 4T1 tumours were grown in Balb/C mice and the AdhspmIL-12 construct was injected intra-tumourally. The tumours were heated after 24 h using a water bath. At various time points post-heating the tumours were collected and quantitatively assessed for cytokine production and vascularity. Results: A significant reduction was seen in the tumour vasculature of the treated group vs. the control group mice. Systemic effects of IL-12 were limited to generalized immunostimulation. No hepatoxicity was noted. Conclusions: This study suggests that IL-12 can be effectively delivered using a gene-based approach with a heat shock promoter. This results in quantitatively measurable anti-angiogenesis and general immunostimulation. The complex inter-play of other pro- and anti-angiogenic factors (IFN-γ, IP-10, VEGF and PAI-1) was also studied.

Original languageEnglish (US)
Pages (from-to)587-606
Number of pages20
JournalInternational Journal of Hyperthermia
Volume22
Issue number7
DOIs
StatePublished - Nov 1 2006

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Keywords

  • Anti-angiogenesis
  • Hyperthermia
  • Interleukin-12

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cancer Research

Cite this

Siddiqui, F., Ehrhart, E. J., Charles, B., Chubb, L., Li, C. Y., Zhang, X., Larue, S. M., Avery, P. R., Dewhirst, M. W., & Ullrich, R. L. (2006). Anti-angiogenic effects of interleukin-12 delivered by a novel hyperthermia induced gene construct. International Journal of Hyperthermia, 22(7), 587-606. https://doi.org/10.1080/02656730600983063