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

Malignant ascites manifests as an end-stage event during the progression of a number of cancers and lacks a generally accepted standard therapy. Interferon- (IFN-) has been used to treat several cancer indications; however, little is known about the efficacy of IFN- on malignant ascites. In the present study, we report on the development of a novel, engineered form of human and murine IFN-, each conjugated with a polyethylene glycol molecule (PEG-hIFN- and PEG-mIFN-, respectively). We provide evidence that these IFN- molecules retain anti-viral potency comparable to unmodified IFN- in vitro and manifested improved pharmacokinetics in vivo. Interestingly, PEG-mIFN- 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- directly suppresses VEGF(165)-induced hyperpermeability in a monolayer of human vascular endothelial cells and that PEG-mIFN- 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- in maintaining vascular integrity, and provide proof-of-mechanism for a novel and long-acting pegylated hIFN- for the therapeutic treatment of malignant ascites.