Identification of biomarkers for the antiangiogenic and antitumour activity of the superoxide dismutase 1 (SOD1) inhibitor tetrathiomolybdate (ATN-224) View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-02-05

AUTHORS

F Doñate, J C Juarez, M E Burnett, M M Manuia, X Guan, D E Shaw, E L P Smith, C Timucin, M J Braunstein, O A Batuman, A P Mazar

ABSTRACT

Tetrathiomolybdate (choline salt; ATN-224), a specific, high-affinity copper binder, is currently being evaluated in several phase II cancer trials. ATN-224 inhibits CuZn superoxide dismutase 1 (SOD1) leading to antiangiogenic and antitumour effects. The pharmacodynamics of tetrathiomolybdate has been followed by tracking ceruloplasmin (Cp), a biomarker for systemic copper. However, at least in mice, the inhibition of angiogenesis occurs before a measurable decrease in systemic copper is observed. Thus, the identification and characterisation of other biomarkers to follow the activity of ATN-224 in the clinic is of great interest. Here, we present the preclinical evaluation of two potential biomarkers for the activity of ATN-224: (i) SOD activity measurements in blood cells in mice and (ii) levels of endothelial progenitor cells (EPCs) in bonnet macaques treated with ATN-224. The superoxide dismutase activity in blood cells in mice is rapidly inhibited by ATN-224 treatment at doses at which angiogenesis is maximally inhibited. Furthermore, ATN-224 dosing in bonnet macaques causes a profound and reversible decrease in EPCs without significant toxicity. Thus, both SOD activity measurements and levels of EPCs may be useful biomarkers of the antiangiogenic activity of ATN-224 to be used in its clinical development. More... »

PAGES

776-783

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.bjc.6604226

DOI

http://dx.doi.org/10.1038/sj.bjc.6604226

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1024901451

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18253124


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