title: Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1.
abstract: The serine protease uPA (urokinase-type plasminogen activator) and its receptor uPAR (CD87) are often elevated in malignant tumours, hence, inhibition of this tumour-associated plasminogen activation system provides an attractive target for therapeutic strategies. WX-UK1, a derivative of 3-aminophenylalanine in the L-conformation with inhibitory antiproteolytic properties, was tested for its specificity spectrum using specific chromogenic paranitroanilide peptide substrates. The corresponding D-enantiomer of WX-UK1 was used as a control. The anti-tumour and anti-metastatic (number of lung foci and weight of the axillary lymph nodes) properties were studied by subcutaneous administration of WX-UK1 to Brown Norwegian (BN) rats carrying orthotopically transplanted BN472 rat breast tumours. WX-UK1 selectively inhibited tumour-related proteases from rats and humans such as uPA, plasmin, or thrombin in the sub or low micromolar range. The activity was stereoselective as the D-enantiomer of WX-UK1 inhibited uPA and plasmin at approximately 70-fold higher Ki values than the active L-form. Chronical administration of the L-enantiomer of WXUK1 impaired primary tumour growth and metastasis of BN472 rat breast cancer in a dose-dependent manner. The minimum inhibitory dosage with maximal effect was between 0.15 and 0.3 mg/kg/day. The inactive D-enatiomer of WX-UK1 was not active in this respect. Daily treatment with WX-UK1 for up to 35 days was well tolerated as judged by the unchanged body and organ weight development. In conclusion, our results provide evidence that WX-UK1 as a single agent inhibits breast tumour growth and metastasis in vivo, and thus is a promising candidate drug to treat human cancer.
authors.affiliation: Department of Medical Oncology, Erasmus Medical Center Rotterdam, 3000 DR Rotterdam, The Netherlands.
authors.forename: Buddy
authors.initials: B
authors.lastname: Setyono-Han
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schmalix
authors.forename: Bernd
authors.initials: B
authors.lastname: Muehlenweg
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.forename: Mieke
authors.initials: M
authors.lastname: Timmermans
authors.forename: Viktor
authors.initials: V
authors.lastname: Magdolen
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012334:RNA, Neoplasm / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D011956:Receptors, Cell Surface / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; C524900:Plaur protein, rat; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010649:Phenylalanine; D014568:Urokinase-Type Plasminogen Activator; C487758:N-alpha-(2,4,6-triisopropyl-phenylsulfonyl)-3-amidino-(L)-phenyl-alanine-4-ethoxycarbonyl-piperazide hydrochloride