Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 2372-2383 |
| Number of pages | 12 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 20 |
| Issue number | 12 |
| Early online date | 8 Oct 2021 |
| DOIs | |
| Publication status | Published - Dec 2021 |
Keywords
- PHASE-I
- MUSTARD
- PR-104A
- COMBINATION
- TH-302
- IDENTIFICATION
- REPAIR
- OXIDOREDUCTASE
- EVOFOSFAMIDE
- DOXORUBICIN
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In: Molecular Cancer Therapeutics, Vol. 20, No. 12, 12.2021, p. 2372-2383.
Research output: Contribution to journal › Article › Academic › peer-review
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 - Funding Information: to Health Innovation Ventures, a patent for AU2013/306514B2 issued and licensed to Health Innovation Ventures, and a patent for US9505791B2 issued and licensed to Health Innovation Ventures. S. Deschoemaeker reports grants from Walloon Region of Belgium and personal fees from Convert Pharmaceuticals during the conduct of the study; also has a patent for WO2019229195A1 pending. M.J. Solivio reports personal fees from Convert Pharmaceuticals during the conduct of the study. J.B. Smaill reports grants from The Health Research Council of New Zealand, Convert Pharmaceuticals, and Health Innovation Ventures during the conduct of the study; personal fees from Convert Pharmaceuticals, Rain Therapeutics, and Kezar Life Sciences; and nonfinancial support from Rain Therapeutics outside the submitted work; also has a patent for EP2888227B1 issued and licensed to Health Innovation Ventures, a patent for US10202408B2 issued and licensed to Health Innovation Ventures, a patent for CA2886574C issued and licensed to Health Innovation Ventures, a patent for US9873710B2 issued and licensed to Health Innovation Ventures, a patent forAU2013/ 306514B2 issued and licensed to Health Innovation Ventures, and a patent for US9505791B2 issued and licensed to Health Innovation Ventures. J. Theys and L.J. Dubois report other support from Convert Pharmaceuticals during the conduct of the study. A.V. Patterson reports grants from Health Research Council of New Zealand and Health Innovation Ventures, grants and personal fees from Convert Pharmaceuticalsduring theconductofthe study;grants, personal fees, and nonfinancial support from Rain Therapeutics outside the submitted work; also has a patent for EP2888227B1 issued and licensed to Health Innovation Ventures, a patent for US10202408B2 issued and licensed to Health Innovation Ventures, a patent for CA2886574C issued and licensed to Health Innovation Ventures, a patent for US9873710B2 issued and licensed to Health Innovation Ventures, a patent forAU2013/ 306514B2 issued and licensed to Health Innovation Ventures, and a patent for US9505791B2 issued and licensed to Health Innovation Ventures. P. Lambin reports other support from Convert Pharmaceuticals during the conduct of the study. No disclosures were reported by the other authors. Funding Information: Prof. M. Losen and Ms. H. Steinbusch from the Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, are greatly acknowledged for their technical support with microscope image acquisition. This work was supported by the Health Research Council of New Zealand (Grant No. 17/255), ERC advanced grant HYPOXIMMUMO (ERC-ADG-2015, no. 694812), Walloon Region of Belgium through the SPW - DG Economie, Emploi, Recherche, its implementing body for regional research and innovation. The authors also acknowledge financial support from the EUROSTARS grant COMPACT (12053) and from Dutch Cancer Society (KWF grant number 8025) and the Cancer Society Auckland Northland, New Zealand (CSAN). Funding Information: A.M. Mowday reports grants from Health Research Council of New Zealand (17/225), Convert Pharmaceuticals, and Health Innovation Ventures during the conduct of the study; also has a patent for EP2888227B1 issued and licensed to Health Innovation Ventures, a patent for US10202408B2 issued and licensed to Health Innovation Ventures, a patent for CA2886574C issued and licensed to Health Innovation Ventures, a patent for US9873710B2 issued and licensed to Health Innovation Ventures, a patent for AU2013/306514B2 issued and licensed to Health Innovation Ventures, and a patent for US9505791B2 issued and licensed to Health Innovation Ventures. X. Lin reports grants from The Health Research Council of New Zealand (17/225), Convert Pharmaceuticals, and Health Innovation Ventures during the conduct of the study. S. Kumara reports grants from Cancer Society of New Zealand during the conduct of the study. A. Ashoorzadeh reports grants from The Health Research Council of New Zealand (17/225), Convert Pharmaceuticals grant, and Health Innovation Ventures grant during the conduct of the study; also has a patent for EP2888227B1 issued and licensed to Health Innovation Ventures, a patent for US10202408B2 issued and licensed to Health Innovation Ventures, a patent for CA2886574C issued and licensed to Health Innovation Ventures, a patent for US9873710B2 issued and licensed to Health Innovation Ventures, a patent forAU2013/ 306514B2 issued and licensed to Health Innovation Ventures, and a patent for US9505791B2 issued and licensed to Health Innovation Ventures. K.O. Hicks reports grants from The Health Research Council of New Zealand (17/225), Convert Pharmaceuticals grant, and Health Innovation Ventures grant during the conduct of the study. M.R. Bull reports grants from The Health Research Council of New Zealand (17/225), Convert Pharmaceuticals, and Health Innovation Ventures during the conduct of the study. C.P. Guise reports grants from The Health Research Council of New Zealand (17/225), Convert Pharmaceuticals, and Health Innovation Ventures during the conduct of the study; in addition, C.P. Guise has a patent for EP2888227B1 issued and licensed to Health Innovation Ventures, a patent for US10202408B2 issued and licensed to Health Innovation Ventures, a patent for CA2886574C issued and licensed to Health Innovation Ventures, a patent for US9873710B2 issued and licensed 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 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.
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 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.
KW - PHASE-I
KW - MUSTARD
KW - PR-104A
KW - COMBINATION
KW - TH-302
KW - IDENTIFICATION
KW - REPAIR
KW - OXIDOREDUCTASE
KW - EVOFOSFAMIDE
KW - DOXORUBICIN
U2 - 10.1158/1535-7163.MCT-21-0406
DO - 10.1158/1535-7163.MCT-21-0406
M3 - Article
C2 - 34625504
SN - 1535-7163
VL - 20
SP - 2372
EP - 2383
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -