Journal
MOLECULAR CANCER THERAPEUTICS
Volume 20, Issue 12, Pages 2372-2383Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0406
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Funding
- Health Research Council of New Zealand [17/255]
- ERC advanced grant HYPOXIMMUMO (ERC-ADG-2015) [694812]
- Walloon Region of Belgium through the SPW -DG Economie, Emploi, Recherche
- EUROSTARS grant COMPACT [12053]
- Dutch Cancer Society (KWF grant) [8025]
- Cancer Society Auckland Northland, New Zealand (CSAN)
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Hypoxia-activated prodrugs (HAP), such as CP-506, have shown promise in selectively targeting hypoxic tumor cells and demonstrating broad antitumor activity. The study revealed that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the drug's antitumor effects.
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 mu mol/L (0.1% O-2). 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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