Novel pegylated interferon-β as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer

Cancer Sci. 2017 Apr;108(4):581-589. doi: 10.1111/cas.13176. Epub 2017 Apr 20.


Malignant ascites manifests as an end-stage event during the progression of a number of cancers and lacks a generally accepted standard therapy. Interferon-β (IFN-β) has been used to treat several cancer indications; however, little is known about the efficacy of IFN-β on malignant ascites. In the present study, we report on the development of a novel, engineered form of human and murine IFN-β, each conjugated with a polyethylene glycol molecule (PEG-hIFN-β and PEG-mIFN-β, respectively). We provide evidence that these IFN-β molecules retain anti-viral potency comparable to unmodified IFN-β in vitro and manifested improved pharmacokinetics in vivo. Interestingly, PEG-mIFN-β significantly inhibited the accumulation of ascites fluid and vascular permeability of the peritoneal membrane in models of ovarian cancer and gastric cancer cell xenograft mice. We further show that PEG-hIFN-β directly suppresses VEGF165 -induced hyperpermeability in a monolayer of human vascular endothelial cells and that PEG-mIFN-β enhanced gene expression for a number of cell adhesion related molecules in mouse vascular endothelial cells. Taken together, these findings unveil a hitherto unrecognized potential of IFN-β in maintaining vascular integrity, and provide proof-of-mechanism for a novel and long-acting pegylated hIFN-β for the therapeutic treatment of malignant ascites.

Keywords: Anti-tumor activity; malignant ascites; pegylated interferon-beta; peritoneal metastasis; vascular hyperpermeability.

MeSH terms

  • 5'-Nucleotidase / metabolism
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology
  • Area Under Curve
  • Ascites / drug therapy*
  • Ascites / pathology
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cells, Cultured
  • Gene Expression / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Interferon-beta / chemistry
  • Interferon-beta / pharmacokinetics
  • Interferon-beta / pharmacology*
  • Metabolic Clearance Rate
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Mice, SCID
  • Oligonucleotide Array Sequence Analysis / methods
  • Peritoneal Neoplasms / drug therapy*
  • Peritoneal Neoplasms / secondary
  • Polyethylene Glycols / chemistry
  • Vascular Endothelial Growth Factor A / pharmacology
  • Xenograft Model Antitumor Assays / methods*


  • Antiviral Agents
  • Vascular Endothelial Growth Factor A
  • Polyethylene Glycols
  • Interferon-beta
  • 5'-Nucleotidase