A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development

FASEB J. 2004 Jan;18(1):161-3. doi: 10.1096/fj.03-0483fje. Epub 2003 Nov 3.

Abstract

The involvement of interleukin-1 (IL-1) in inflammation, tumor growth, and metastasis makes it an attractive target for therapeutic intervention. Here, we show that a continuous delivery of a low, but steady-state level of the naturally occurring IL-1 receptor antagonist (IL-1Ra) reduced inflammatory responses and inhibited tumor development in mice, phenomena that are induced by IL-1, mainly secretable IL-1beta. The IL-1Ra was delivered from microencapsulated genetically engineered cells, which overexpress and secrete this mediator. For a tumor model, we used fibrosarcoma cell line, which secretes high levels of IL-1beta; when injected s.c. into mice, the cells developed into large tumors characterized by very active angiogenic patterns. The proangiogenic features of IL-1beta were manifested at low levels of the cytokine, and release of 25 ng per day of the IL-1Ra was needed to oppose its effects and inhibit tumor development. The continuous delivery of the IL-1Ra contributed to improved biocompatibility of the microencapsulated cell systems; the fibrotic sac surrounding the systems was much thinner with significantly less blood capillaries and inflammatory cells. Not only do our findings point to the antiangiogenic properties of IL-1Ra in inflammation and tumor growth, but they also provide a more efficient and convenient way for treating diseases involving IL-1.

MeSH terms

  • Animals
  • Cell Division
  • Cell Line, Tumor
  • Cell Transplantation / methods*
  • Genetic Engineering
  • Interleukin 1 Receptor Antagonist Protein
  • Mice
  • Microspheres
  • NIH 3T3 Cells
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy*
  • Neovascularization, Pathologic*
  • Sialoglycoproteins / genetics*
  • Survival Analysis

Substances

  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Sialoglycoproteins