Suppression of Angiogenesis and Therapy of Human Colon Cancer Liver Metastasis by Systemic Administration of Interferon-Alpha

Neoplasia. Mar-Apr 2001;3(2):154-64. doi: 10.1038/sj.neo.7900128.

Abstract

The purpose of this study was to determine whether systemic administration of interferon-alpha (IFN-alpha) can inhibit liver metastasis produced in nude mice by human colon cancer cells. KM12L4 (IFN-alpha-sensitive) or KM12L4 IFN(R) (IFN-alpha-resistant) cells were injected into the spleen of nude mice. Seven days later, the mice were treated with subcutaneous (s.c.) injections of IFN-alpha (70,000 units/week) at different dosing schedules (1, 2, or 7 times/week). Significant inhibition of tumor growth, vascularization and expression of basic fibroblast growth factor (bFGF) or matrix metalloproteinase-9 (MMP-9) mRNA and protein occurred in mice given daily injections of IFN-alpha. Kinetic analysis of therapy showed that daily s.c. administrations of 10,000 units of IFN-alpha induced apoptosis in liver metastasis-associated endothelial cells, followed by inhibition of tumor cell division and apoptosis of tumor cells. These data suggest that the antiangiogenic activity of IFN-alpha-2a depends on frequent administration of the optimal biologic dose.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Fibroblast Growth Factor 2 / biosynthesis
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Interferon Type I / therapeutic use*
  • Interferon alpha-2
  • Interferon-alpha / therapeutic use*
  • Kinetics
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / secondary*
  • Male
  • Matrix Metalloproteinase 8 / biosynthesis
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Neovascularization, Pathologic*
  • Platelet Endothelial Cell Adhesion Molecule-1 / biosynthesis
  • Proliferating Cell Nuclear Antigen / biosynthesis
  • RNA, Messenger / metabolism
  • Recombinant Proteins
  • Spleen / metabolism
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Interferon Type I
  • Interferon alpha-2
  • Interferon-alpha
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Proliferating Cell Nuclear Antigen
  • RNA, Messenger
  • Recombinant Proteins
  • Fibroblast Growth Factor 2
  • Matrix Metalloproteinase 8