Abstract
We have designed a molecule, GFB-111, that binds to platelet-derived growth factor (PDGF), prevents it from binding to its receptor tyrosine kinase, and blocks PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases, and DNA synthesis. GFB-111 is highly potent (IC50 = 250 nM) and selective for PDGF over EGF, IGF-1, aFGF, bFGF, and HRGbeta (IC50 values > 100 microM), but inhibits VEGF-induced Flk-1 tyrosine phosphorylation and Erk1/Erk2 activation with an IC50 of 10 microM. GFB-111 treatment of nude mice bearing human tumors resulted in significant inhibition of tumor growth and angiogenesis. The results demonstrate the feasibility of designing novel growth factor-binding molecules with potent anticancer and antiangiogenic activity.
Publication types
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Angiogenesis Inhibitors / chemistry
-
Angiogenesis Inhibitors / metabolism
-
Angiogenesis Inhibitors / pharmacology
-
Angiogenesis Inhibitors / therapeutic use*
-
Animals
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / metabolism
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use*
-
Cell Division / drug effects
-
Cell Line
-
DNA / biosynthesis
-
Drug Design*
-
Endothelial Growth Factors / antagonists & inhibitors
-
Endothelial Growth Factors / pharmacology
-
Enzyme Activation / drug effects
-
Glioblastoma / blood supply
-
Glioblastoma / drug therapy*
-
Glioblastoma / pathology
-
Humans
-
Inhibitory Concentration 50
-
Lymphokines / antagonists & inhibitors
-
Lymphokines / pharmacology
-
Mice
-
Mice, Nude
-
Mitogen-Activated Protein Kinases / metabolism
-
Neoplasm Transplantation
-
Neovascularization, Pathologic / drug therapy
-
Peptides, Cyclic / chemistry
-
Peptides, Cyclic / metabolism
-
Peptides, Cyclic / pharmacology*
-
Peptides, Cyclic / therapeutic use
-
Phosphorylation / drug effects
-
Platelet-Derived Growth Factor / antagonists & inhibitors*
-
Platelet-Derived Growth Factor / metabolism
-
Platelet-Derived Growth Factor / pharmacology
-
Receptor Protein-Tyrosine Kinases / metabolism
-
Receptors, Growth Factor / metabolism
-
Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
-
Receptors, Platelet-Derived Growth Factor / metabolism
-
Receptors, Vascular Endothelial Growth Factor
-
Substrate Specificity
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
Substances
-
Angiogenesis Inhibitors
-
Antineoplastic Agents
-
Endothelial Growth Factors
-
GFB 111
-
Lymphokines
-
Peptides, Cyclic
-
Platelet-Derived Growth Factor
-
Receptors, Growth Factor
-
Vascular Endothelial Growth Factor A
-
Vascular Endothelial Growth Factors
-
DNA
-
Receptor Protein-Tyrosine Kinases
-
Receptors, Platelet-Derived Growth Factor
-
Receptors, Vascular Endothelial Growth Factor
-
Mitogen-Activated Protein Kinases