Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1

Buddy Setyono-Han; Jörg Stürzebecher; Wolfgang A. Schmalix; Bernd Muehlenweg; Anieta M. Sieuwerts; Mieke Timmermans; Viktor Magdolen; Manfred Schmitt; Jan G. M. Klijn; John A. Foekens

doi:10.1160/TH04-11-0712

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 93(04): 779-786
DOI: 10.1160/TH04-11-0712

Cellular Proteolysis and Oncology

Schattauer GmbH

Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1

Authors

Buddy Setyono-Han

¹Department of Medical Oncology, Erasmus Medical Center Rotterdam, The Netherlands
Jörg Stürzebecher

²Klinikum der Universität Jena, Zentrum für Vaskuläre Biologie und Medizin, Erfurt, Germany
Wolfgang A. Schmalix

³Wilex AG, Munich, Germany
Bernd Muehlenweg

³Wilex AG, Munich, Germany
Anieta M. Sieuwerts

¹Department of Medical Oncology, Erasmus Medical Center Rotterdam, The Netherlands
Mieke Timmermans

¹Department of Medical Oncology, Erasmus Medical Center Rotterdam, The Netherlands
Viktor Magdolen

⁴Klinische Forschergruppe, Frauenklinik der Technische Universität München, Klinikum rechts der Isar, Munich, Germany
Manfred Schmitt

⁴Klinische Forschergruppe, Frauenklinik der Technische Universität München, Klinikum rechts der Isar, Munich, Germany
Jan G. M. Klijn

¹Department of Medical Oncology, Erasmus Medical Center Rotterdam, The Netherlands
John A. Foekens

¹Department of Medical Oncology, Erasmus Medical Center Rotterdam, The Netherlands

Abstract

Summary

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 plas-min at approximately 70-fold higher K_i 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.

Keywords

Urokinase-type plasminogen activator (uPA) - synthetic uPA-inhibitor - rat mammary carcinoma - anti-metastatic treatment - serine protease

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Referenzen

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