TY - JOUR
T1 - High-affinity urokinase-derived cyclic peptides inhibiting urokinase/urokinase receptor-interaction
T2 - Effects on tumor growth and spread
AU - Sato, Sumito
AU - Kopitz, Charlotte
AU - Schmalix, Wolfgang A.
AU - Muehlenweg, Bernd
AU - Kessler, Horst
AU - Schmitt, Manfred
AU - Krüger, Achim
AU - Magdolen, Viktor
N1 - Funding Information:
Part of this work was supported by grants of the Sonderforschungsbereich 469 (A4, B13) and the Sonderforschungsbereich 456 (B9) of the Deutsche Forschungsgemeinschaft (DFG), and Wilex AG, München.
PY - 2002/9/25
Y1 - 2002/9/25
N2 - 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 (uPA19-31). 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 (cyclo21,29[D-Cys21]-uPA21-30[S21C;H29C]) and its norleucine (Nle) derivative WX-360-Nle (cyclo21,29[D-Cys21]-uPA21-30[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.
AB - 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 (uPA19-31). 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 (cyclo21,29[D-Cys21]-uPA21-30[S21C;H29C]) and its norleucine (Nle) derivative WX-360-Nle (cyclo21,29[D-Cys21]-uPA21-30[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.
KW - Cancer
KW - Competitive uPA-derived peptide antagonists
KW - Urokinase-type plasminogen activator
UR - http://www.scopus.com/inward/record.url?scp=0037174147&partnerID=8YFLogxK
U2 - 10.1016/S0014-5793(02)03311-2
DO - 10.1016/S0014-5793(02)03311-2
M3 - Article
C2 - 12297307
AN - SCOPUS:0037174147
SN - 0014-5793
VL - 528
SP - 212
EP - 216
JO - FEBS Letters
JF - FEBS Letters
IS - 1-3
ER -
