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Br J Cancer ; 98(4): 776-83, 2008 Feb 26.
Article in English | MEDLINE | ID: mdl-18253124

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.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Biomarkers/metabolism , Endothelium, Vascular/drug effects , Enzyme Inhibitors/pharmacology , Molybdenum/pharmacology , Superoxide Dismutase/antagonists & inhibitors , Animals , Blood Cells/drug effects , Blood Cells/metabolism , Collagen/metabolism , Copper/metabolism , Drug Combinations , Female , Laminin/metabolism , Macaca radiata , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Proteoglycans/metabolism , Stem Cells/drug effects , Superoxide Dismutase/metabolism , Superoxide Dismutase-1
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