title: 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 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.
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Iwamura
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Narumi
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Mori
authors.affiliation: Pharmaceuticals Technical Development Department, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Pharmaceuticals Technical Development Department, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tsushima
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Asano
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Izawa
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Momen
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tsuchiyama
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Uchida
authors.affiliation: Pharmaceuticals Technical Development Department, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Pharmaceutical Research Laboratory, Toray Industries, Kamakura, Kanagawa, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Okano
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo, Japan.
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001201:Ascites / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008657:Metabolic Clearance Rate; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D011092:Polyethylene Glycols / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000998:Antiviral Agents; D042461:Vascular Endothelial Growth Factor A; D011092:Polyethylene Glycols; D016899:Interferon-beta; D015720:5'-Nucleotidase
keywords: Anti-tumor activity; malignant ascites; pegylated interferon-beta; peritoneal metastasis; vascular hyperpermeability