Novel pegylated interferon-ß 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-ß (IFN-ß) has been used to treat several cancer indications; however, little is known about the efficacy of IFN-ß on malignant ascites. In the present study, we report on the development of a novel, engineered form of human and murine IFN-ß, each conjugated with a polyethylene glycol molecule (PEG-hIFN-ß and PEG-mIFN-ß, respectively). We provide evidence that these IFN-ß molecules retain anti-viral potency comparable to unmodified IFN-ß in vitro and manifested improved pharmacokinetics in vivo. Interestingly, PEG-mIFN-ß 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-ß directly suppresses VEGF165 -induced hyperpermeability in a monolayer of human vascular endothelial cells and that PEG-mIFN-ß 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-ß in maintaining vascular integrity, and provide proof-of-mechanism for a novel and long-acting pegylated hIFN-ß for the therapeutic treatment of malignant ascites.