High‐affinity urokinase‐derived cyclic peptides inhibiting urokinase/urokinase receptor‐interaction: effects on tumor growth and spread

FEBS Letters

Sato, Sumito²  Kessler, Horst³  Schmitt, Manfred²  Muehlenweg, Bernd¹  Kopitz, Charlotte⁴  Magdolen, Viktor²  Schmalix, Wolfgang A¹  Krüger, Achim⁴ 

[1] Wilex AG, München, Germany;Klinische Forschergruppe der Frauenklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, D-81675 München, Germany;Institut für Organische Chemie und Biochemie, Technische Universität München, München, Germany;Institut für Experimentelle Onkologie und Therapieforschung der Technischen Universität München, München, Germany

关键词: Urokinase-type plasminogen activator;    Competitive uPA-derived peptide antagonists;    Cancer;   

DOI  :  10.1016/S0014-5793(02)03311-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown