TY - JOUR
T1 - Selectively targeting tumor hypoxia with the hypoxia-activated prodrug CP-506
AU - van der Wiel, Alexander M.A.
AU - Jackson-Patel, Victoria
AU - Niemans, Raymon
AU - Yaromina, Ala
AU - Liu, Emily
AU - Marcus, Damiënne
AU - Mowday, Alexandra M.
AU - Lieuwes, Natasja G.
AU - Biemans, Rianne
AU - Lin, Xiaojing
AU - Fu, Zhe
AU - Kumara, Sisira
AU - Jochems, Arthur
AU - Ashoorzadeh, Amir
AU - Anderson, Robert F.
AU - Hicks, Kevin O.
AU - Bull, Matthew R.
AU - Abbattista, Maria R.
AU - Guise, Christopher P.
AU - Deschoemaeker, Sofie
AU - Thiolloy, Sophie
AU - Heyerick, Arne
AU - Solivio, Morwena J.
AU - Balbo, Silvia
AU - Smaill, Jeff B.
AU - Theys, Jan
AU - Dubois, Ludwig J.
AU - Patterson, Adam V.
AU - Lambin, Philippe
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/12
Y1 - 2021/12
N2 - 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 mmol/L (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 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.
AB - 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 mmol/L (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 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.
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U2 - 10.1158/1535-7163.MCT-21-0406
DO - 10.1158/1535-7163.MCT-21-0406
M3 - Article
C2 - 34625504
AN - SCOPUS:85119964916
SN - 1535-7163
VL - 20
SP - 2372
EP - 2383
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -
