Open AccessSelectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506
Author(s) -
Alexander M.A. van der Wiel,
Victoria Jackson-Patel,
Raymon Niemans,
Ala Yaromina,
Emily Liu,
Damiënne Marcus,
Alexandra M. Mowday,
Natasja G. Lieuwes,
Rianne Biemans,
Xiaojing Lin,
Zhe Fu,
Sisira Kumara,
Arthur Jochems,
Amir Ashoorzadeh,
Robert F. Anderson,
Kevin O. Hicks,
Matthew R. Bull,
Maria R. Abbattista,
Christopher P. Guise,
Sofie Deschoemaeker,
Sophie Thiolloy,
Arne Heyerick,
Morwena J. Solivio,
Silvia Balbo,
Jeff B. Smaill,
Jan Theys,
Ludwig Dubois,
Adam V. Patterson
Publication year - 2021
Publication title -
molecular cancer therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.717
H-Index - 173
eISSN - 1538-8514
pISSN - 1535-7163
DOI - 10.1158/1535-7163.mct-21-0406
Subject(s) - hypoxia (environmental) , prodrug , cytotoxicity , tumor hypoxia , in vivo , chemistry , in vitro , reactive oxygen species , metabolism , tirapazamine , pharmacology , biology , biochemistry , oxygen , medicine , microbiology and biotechnology , organic chemistry , radiation therapy
Hypoxia-activated prodrugs (HAP) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. This study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacologic properties. Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods with observed parameters fulfilling requirements for oxygen-sensitive bioactivation. Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 μmol/L (0.1% O 2 ). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC 50 ratios up to 203. Complete resistance to aerobic (two-electron) metabolism by aldo-keto reductase 1C3 was confirmed through gain-of-function studies while retention of hypoxic (one-electron) bioactivation by various diflavin oxidoreductases was also demonstrated. In vivo , the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 were significantly correlated with treatment response. Our results demonstrate that CP-506 selectively targets hypoxic tumor cells and has broad antitumor activity. Our data indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.