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Urokinase receptor antagonists: discovery and application to in vivo models of tumor growth
Author(s) -
TRESSLER ROBERT J.,
PITOT PATRICE A.,
STRATTON JENNIFER R.,
FORREST LOUISE D.,
ZHUO SHAOQIU,
DRUMMOND ROBERT J.,
FONG SUSAN,
DOYLE MICHAEL V.,
DOYLE LAURA V.,
MIN HYE YEONG,
ROSENBERG STEVEN
Publication year - 1999
Publication title -
apmis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.909
H-Index - 88
eISSN - 1600-0463
pISSN - 0903-4641
DOI - 10.1111/j.1699-0463.1999.tb01540.x
Subject(s) - in vivo , urokinase receptor , urokinase , receptor , medicine , computational biology , cancer research , pharmacology , biology , microbiology and biotechnology
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.