Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506

Autor: Arthur Jochems, Jeff B. Smaill, Christopher P. Guise, Arne Heyerick, Maria R. Abbattista, Sophie Thiolloy, Amir Ashoorzadeh, Alexander M A van der Wiel, Kevin O. Hicks, Jan Theys, Ludwig Dubois, Philippe Lambin, Xiaojing Lin, Emily Liu, Robert F. Anderson, Zhe Fu, Damiënne Marcus, Victoria Jackson-Patel, Adam V. Patterson, Sisira Kumara, Ala Yaromina, Matthew Bull, Silvia Balbo, Morwena J. Solivio, R. Biemans, Sofie Deschoemaeker, Raymon Niemans, Alexandra M. Mowday, Natasja G. Lieuwes
Přispěvatelé: Cellular and Molecular Immunology, Precision Medicine, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, RS: GROW - R2 - Basic and Translational Cancer Biology
Rok vydání: 2021
Předmět:
Zdroj: Molecular Cancer Therapeutics, 20(12), 2372-2383. American Association for Cancer Research Inc.
ISSN: 1538-8514
1535-7163
Popis: Background Hypoxia-activated prodrugs (HAPs) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. The present study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacological properties. Methods Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods. In vitro, 2D monolayer and 3D spheroid and multicellular layer cultures were used to investigate the hypoxia-selectivity of CP-506. In vivo, the causal relationship between tumor oxygenation and antitumor effects of CP-506 was assessed. Mice bearing a range of human tumor xenografts were exposed to CP-506 and tumor growth was monitored. A multivariate linear regression model was used to identify factors associated with CP-506 treatment outcome. Results Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 µM (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. 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. Two well-oxygenated models were refractory to treatment despite intrinsic anoxic sensitivity in vitro. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 to significantly correlate with treatment response. Conclusions Our results demonstrate that CP-506 selectively sterilizes hypoxic tumor cells and has broad antitumor activity. Our data also indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.
Databáze: OpenAIRE
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