Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model.
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.
Schurigt
Uta
U
Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, D-79104 Freiburg, Germany.
Sevenich
Lisa
L
Vannier
Corinne
C
Gajda
Mieczyslaw
M
Schwinde
Anne
A
Werner
Fee
F
Stahl
Andreas
A
von Elverfeldt
Dominik
D
Becker
Anne-Katrin
AK
Bogyo
Matthew
M
Peters
Christoph
C
Reinheckel
Thomas
T
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007930:Leucine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging
D015853:Cysteine Proteinase Inhibitors; C404948:JPM 565; D002403:Cathepsins; D007930:Leucine