In:
FEBS Letters, Wiley, Vol. 528, No. 1-3 ( 2002-09-25), p. 212-216
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0014-5793
,
1873-3468
DOI:
10.1016/S0014-5793(02)03311-2
Language:
English
Publisher:
Wiley
Publication Date:
2002
detail.hit.zdb_id:
1460391-3
SSG:
12
