Urokinase receptor antagonists: discovery and application to in vivo models of tumor growth.
Urokinase receptor antagonists based on the growth factor domains of both human and murine urokinase which show sub-nanomolar affinities for their homologous receptors have been expressed as recombinant proteins. Further modification of these molecules by preparing fusions with the constant region of human IgG has led to molecules with high affinities and long in vivo half-lives. Smaller peptidic inhibitors have been obtained by a combination of bacteriophage display and peptide analog synthesis. All of these molecules inhibit the binding of the growth factor domain of uPA to the uPA receptor and enhance binding of the uPA receptor to vitronectin. Protein uPA receptor antagonists were tested in an in vivo tumor model using the human breast carcinoma MDAmb231 in immunodeficient mice. Both human and murine receptor antagonists showed significant inhibition of primary tumor growth, demonstrating that in vivo, both tumor and stromal cell uPA receptor dependent plasminogen activation can modulate tumor growth.
Tressler
R J
RJ
Chiron Corporation, Emeryville, California 94608, USA.
Pitot
P A
PA
Stratton
J R
JR
Forrest
L D
LD
Zhuo
S
S
Drummond
R J
RJ
Fong
S
S
Doyle
M V
MV
Doyle
L V
LV
Min
H Y
HY
Rosenberg
S
S
D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin / Q000378:metabolism
C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin