Flk-1 specific kinase inhibitor (SU5416) inhibited the growth of GS-9L glioma in rat brain and prolonged the survival

Kobe J Med Sci. 2001 Aug;47(4):181-91.

Abstract

Background: Accumulating evidences suggest that tumor growth and metastasis depend on angiogenesis. At present, plenty of efforts are made to discover a chemical compound that specifically inhibits tumor angiogenesis either by reducing pro-angiogenic factor or increasing anti-angiogenic factors.

Object: SU5416, a novel, synthetic, potential inhibitor of angiogenesis specifically blocks the Flk-1/KDR tyrosine kinase activity. In vivo effect of SU5416 in the treatment of intracranial tumors has not been previously described.

Methods: We transplanted GS-9L cells into the right caudate nucleus of male Fisher 344 rats and administrated SU5416 intraperitoneally (i.p.) to investigate the impact of SU5416 on tumor angiogenesis and growth in vivo. Starting on Day 1 or Day 8, forty-two animals were treated with SU5416 at three different doses (e.g. 12.5, 25.0 and 50.0 mg/kg body weight) via i.p. injection every day until the end-point. As a control, seven animals received no treatment and after implant fourteen animals were treated with vehicle (DMSO) only.

Results: SU5416 prolonged the survival in the treated groups without any significant systemic adverse effect. Median survival in the treated group started on Day.1 was statistically longer compared to that in the control groups (p<0.01). Histological analysis of the treated tumors showed an increase in necroses and reduced in vascularity compared to the control tumors. Furthermore, the number of apoptotic cells increased in the treated tumors on a TUNEL stain.

Conclusion: Small molecular compounds, such as SU5416 may be useful therapeutics that specifically inhibits the enzymatic activity of Flk-1 kinase and downstream events of tumor angiogenesis.

MeSH terms

  • Animals
  • Apoptosis
  • Brain / blood supply
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Enzyme Inhibitors / therapeutic use*
  • Enzyme Inhibitors / toxicity
  • Glioma / drug therapy*
  • Glioma / mortality
  • Glioma / pathology
  • Indoles / therapeutic use*
  • Indoles / toxicity
  • Male
  • Microcirculation / pathology
  • Pyrroles / therapeutic use*
  • Pyrroles / toxicity
  • Rats
  • Rats, Inbred F344
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptors, Growth Factor / antagonists & inhibitors*
  • Receptors, Vascular Endothelial Growth Factor
  • Survival Rate

Substances

  • Enzyme Inhibitors
  • Indoles
  • Pyrroles
  • Receptors, Growth Factor
  • Semaxinib
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor