BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity.
Matrix metalloproteinases (MMPs) have been implicated in tumor cell invasion, metastasis, and angiogenesis. BAY 12-9566, a novel, non-peptidic biphenyl MMP inhibitor, has shown preclinical activity on a broad range of tumor models and is currently in clinical development. The purpose of this study was to investigate the antiangiogenic activity of BAY 12-9566. In vitro, BAY 12-9566 prevented matrix invasion by endothelial cells in a concentration-dependent manner (IC50 = 8.4x10(-7) M), without affecting cell proliferation. In vivo, oral daily administration of BAY 12-9566 (50-200 mg/kg) inhibited angiogenesis induced by basic fibroblast growth factor in the Matrigel plug assay, reducing the hemoglobin content of the pellets. Histological analysis showed a reduction in the amount of functional vessels within the Matrigel. We conclude that the MMP inhibitor BAY 12-9566 inhibits angiogenesis, a property that further supports its clinical development as an antimetastatic agent.
Gatto
C
C
Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Rieppi
M
M
Borsotti
P
P
Innocenti
S
S
Ceruti
R
R
Drudis
T
T
Scanziani
E
E
Casazza
A M
AM
Taraboletti
G
G
Giavazzi
R
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009930:Organic Chemicals; D010654:Phenylbutyrates; D011509:Proteoglycans; D014471:Umbilical Veins
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D004338:Drug Combinations; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; D011509:Proteoglycans; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; C113281:Bay 12-9566