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High‐affinity urokinase‐derived cyclic peptides inhibiting urokinase/urokinase receptor‐interaction: effects on tumor growth and spread
Author(s) -
Sato Sumito,
Kopitz Charlotte,
Schmalix Wolfgang A,
Muehlenweg Bernd,
Kessler Horst,
Schmitt Manfred,
Krüger Achim,
Magdolen Viktor
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)03311-2
Subject(s) - urokinase receptor , urokinase , plasminogen activator , chemistry , in vivo , cancer research , ovarian cancer , receptor , ovarian tumor , microbiology and biotechnology , biology , cancer , biochemistry , endocrinology , medicine
Urokinase‐type plasminogen activator (uPA) binds with high affinity to its specific cell surface receptor (uPAR) (CD87) via a well‐defined sequence within the N‐terminal region of uPA (uPA 19–31 ). Since this uPA/uPAR‐interaction plays a significant role in tumor cell invasion and metastasis, it has become an attractive therapeutic target. Two small peptidic cyclic competitive antagonists of uPA/uPAR‐interaction have been developed, based on the uPAR binding site in uPA: WX‐360 (cyclo 21,29 [ D ‐Cys21]‐uPA 21–30 [S21C;H29C]) and its norleucine (Nle) derivative WX‐360‐Nle (cyclo 21,29 [ D ‐Cys21]‐uPA 21–30 [S21C;K23Nle;H29C]). These peptides display an only five to 10‐fold lower affinity to uPAR as compared to the naturally occurring uPAR‐ligand uPA. In this study, WX‐360 and WX‐360‐Nle were tested in nude mice for their potency to inhibit tumor growth and intraperitoneal spread of lacZ ‐tagged human ovarian cancer cells. Intraperitoneal administration of either cyclic peptide (20 mg peptide/kg; 1× daily for 37 days) into the tumor‐bearing nude mice resulted in a significant reduction of tumor weight and spread within the peritoneum as compared to the untreated control group. This is the first report demonstrating effective reduction of tumor growth and spread of human ovarian cancer cells in vivo by small synthetic uPA‐derived cyclic peptides competitively interfering with uPA/uPAR‐interaction. Thus, both WX‐360 and WX‐360‐Nle are promising novel compounds to reduce dissemination of human ovarian carcinoma.