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

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

Author information

1
Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
2
Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.
3
Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo, Japan.
4
Pharmaceuticals Technical Development Department, Toray Industries, Kamakura, Kanagawa, Japan.

Abstract

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

PMID:
28129467
PMCID:
PMC5406538
DOI:
10.1111/cas.13176
[Indexed for MEDLINE]
Free PMC Article

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