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

Alexander M A van der Wiel, Victoria Jackson-Patel, Raymon Niemans, Ala Yaromina, Emily Liu, Damiënne Marcus, Alexandra M Mowday, Natasja G Lieuwes, Rianne Biemans, Xiaojing Lin, Zhe Fu, Sisira Kumara, Arthur Jochems, Amir Ashoorzadeh, Robert F Anderson, Kevin O Hicks, Matthew R Bull, Maria R Abbattista, Christopher P Guise, Sofie DeschoemaekerSophie Thiolloy, Arne Heyerick, Morwena J Solivio, Silvia Balbo, Jeff B Smaill, Jan Theys, Ludwig J Dubois, Adam V Patterson*, Philippe Lambin

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)

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 languageEnglish
Pages (from-to)2372-2383
Number of pages12
JournalMolecular Cancer Therapeutics
Volume20
Issue number12
Early online date8 Oct 2021
DOIs
Publication statusPublished - Dec 2021

Keywords

  • PHASE-I
  • MUSTARD
  • PR-104A
  • COMBINATION
  • TH-302
  • IDENTIFICATION
  • REPAIR
  • OXIDOREDUCTASE
  • EVOFOSFAMIDE
  • DOXORUBICIN

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