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., ...Daha Fazla

BRITISH JOURNAL OF CANCER, cilt.98, sa.4, ss.776-783, 2008 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 98 Sayı: 4
  • Basım Tarihi: 2008
  • Doi Numarası: 10.1038/sj.bjc.6604226
  • Dergi Adı: BRITISH JOURNAL OF CANCER
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.776-783
  • Anahtar Kelimeler: biomarkers, angiogenesis, superoxide dismutase, tetrathiomolybdate, circulating progenitor cells, EXTRACELLULAR-SUPEROXIDE DISMUTASE, ANGIOGENESIS, CANCER, THERAPY
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Hayır

Özet

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.