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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model

Uta Schurigt1a / Lisa Sevenich2a / Corinne Vannier3 / Mieczyslaw Gajda4 / Anne Schwinde5 / Fee Werner6 / Andreas Stahl7 / Dominik von Elverfeldt8 / Anne-Katrin Becker9 / Matthew Bogyo10 / Christoph Peters11 / Thomas Reinheckel12

1Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany

2Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany

3Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany

4Institut für Pathologie, Friedrich-Schiller-Universität Jena, D-07740 Jena, Germany

5Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany

6Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany

7Universitäts-Augenklinik, Albert-Ludwigs-Universität Freiburg, D-79106 Freiburg, Germany

8Abteilung Röntgendiagnostik Medizin Physik, Albert-Ludwigs-Universität Freiburg, D-79106 Freiburg, Germany

9Abteilung Röntgendiagnostik Medizin Physik, Albert-Ludwigs-Universität Freiburg, D-79106 Freiburg, Germany

10Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA

11Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany

12Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany

Corresponding author

Citation Information: Biological Chemistry. Volume 389, Issue 8, Pages 1067–1074, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2008.115, August 2008

Publication History

Received:
2007-12-17
Accepted:
2008-03-27
Published Online:
2008-08-19

Abstract

Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection of JPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, which result in poor bioavailability, may prohibit its use for stand-alone treatment of solid mammary cancers and their lung metastases.

Keywords: pharmacokinetics; protease inhibitor; therapy

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