Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506
| العنوان: | Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506 |
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| المؤلفون: | 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 |
| المساهمون: | Cellular and Molecular Immunology, Precision Medicine, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Radiotherapie, RS: GROW - R2 - Basic and Translational Cancer Biology |
| المصدر: | Molecular Cancer Therapeutics, 20(12), 2372-2383. American Association for Cancer Research Inc. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, DOXORUBICIN, Reductase, Mice, In vivo, Animals, Humans, Prodrugs, OXIDOREDUCTASE, Cytotoxicity, COMBINATION, TH-302, REPAIR, Tumor hypoxia, IDENTIFICATION, Chemistry, Tumor Oxygenation, Prodrug, PR-104A, In vitro, PHASE-I, Oncology, Cell culture, Cancer research, MUSTARD, EVOFOSFAMIDE, Tumor Hypoxia |
| الوصف: | 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. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8da436b0cdc3474a21aab13146be81dd https://pubmed.ncbi.nlm.nih.gov/34625504 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8da436b0cdc3474a21aab13146be81dd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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