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

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 VEGF 165‐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.

Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance

“…Indeed, pegylated type I IFNs showed therapeutic efficacy in different preclinical models of cancer ( 48 , 49 ). More recently, pegylated IFN-β was shown to significantly inhibit the vascular permeability of the peritoneal membrane in animal models of ovarian cancer and gastric cancer cell xenograft mice ( 50 ). In the clinical setting, however, unlike what observed in patients with chronic viral infections, the use of pegylated type I IFNs was associated with limited benefit.…”

Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway

“…Tumor cells can excrete many types of cytokines, such as VEGFA and TNF-α, thereby altering the permeability of microvascular networks and causing transudative and exudative ascites 43 , 44 . Macrophage and inflammatory cells could induce pyroptosis or necroptosis, release several necrotic materials and inflammatory mediators, and increase the volume of ascites 8 , 45 .…”

Molecular biology and immunology of gastric cancer peritoneal metastasis

“…The essential nature of interferonactivated immune signaling and its role in stimulation of immune effector cell functions for tumor prevention or eradication has been established in murine models. Novel engineered forms of human and mouse IFN-β have been developed, named PEG-hIFN-β and PEG-mIFN-β, in which IFN-β is conjugated with a polyethylene glycol (89). These IFN-β molecules retained anti-viral potency similar to natural IFN-β in vitro and manifested improved pharmacokinetics in vivo.…”