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


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Donate F., Juarez J. C. , Burnett M. E. , Manuia M. M. , Guan X., Shaw D. E. , ...More

BRITISH JOURNAL OF CANCER, vol.98, no.4, pp.776-783, 2008 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 98 Issue: 4
  • Publication Date: 2008
  • Doi Number: 10.1038/sj.bjc.6604226
  • Title of Journal : BRITISH JOURNAL OF CANCER
  • Page Numbers: pp.776-783
  • Keywords: biomarkers, angiogenesis, superoxide dismutase, tetrathiomolybdate, circulating progenitor cells, EXTRACELLULAR-SUPEROXIDE DISMUTASE, ANGIOGENESIS, CANCER, THERAPY

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.