Document Detail


Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302.
MedLine Citation:
PMID:  22147748     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) of bromo-isophosphoramide mustard currently undergoing clinical evaluation. Here, we describe broad-spectrum activity, hypoxia-selective activation, and mechanism of action of TH-302. The concentration and time dependence of TH-302 activation was examined as a function of oxygen concentration, with reference to the prototypic HAP tirapazamine, and showed superior oxygen inhibition of cytotoxicity and much improved dose potency relative to tirapazamine. Enhanced TH-302 cytotoxicity under hypoxia was observed across 32 human cancer cell lines. One-electron reductive enzyme dependence was confirmed using cells overexpressing human NADPH:cytochrome P450 oxidoreductase and radiolytic reduction established the single-electron stoichiometry of TH-302 fragmentation (activation). Examining downstream effects of TH-302 activity, we observed hypoxia-dependent induction of γH2AX phosphorylation, DNA cross-linking, and cell-cycle arrest. We used Chinese hamster ovary cell-based DNA repair mutant cell lines and established that lines deficient in homology-dependent repair, but not lines deficient in base excision, nucleotide excision, or nonhomologous end-joining repair, exhibited marked sensitivity to TH-302 under hypoxia. Consistent with this finding, enhanced sensitivity to TH-302 was also observed in lines deficient in BRCA1, BRCA2, and FANCA. Finally, we characterized TH-302 activity in the three-dimensional tumor spheroid and multicellular layer models. TH-302 showed much enhanced potency in H460 spheroids compared with H460 monolayer cells under normoxia. Multicellular layers composed of mixtures of parental HCT116 cells and HCT116 cells engineered to express an oxygen-insensitive bacterial nitroreductase showed that TH-302 exhibits a significant bystander effect.
Authors:
Fanying Meng; James W Evans; Deepthi Bhupathi; Monica Banica; Leslie Lan; Gustavo Lorente; Jian-Xin Duan; Xiaohong Cai; Alexandra M Mowday; Christopher P Guise; Andrej Maroz; Robert F Anderson; Adam V Patterson; Gregory C Stachelek; Peter M Glazer; Mark D Matteucci; Charles P Hart
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-12-06
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  11     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-08     Completed Date:  2012-07-09     Revised Date:  2014-04-24    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  740-51     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
CHO Cells
Cell Hypoxia
Cell Line, Tumor
Cell Survival / drug effects
Comet Assay
Cricetinae
Cricetulus
DNA Damage
Dose-Response Relationship, Drug
HCT116 Cells
HT29 Cells
Histones / metabolism
Humans
Inhibitory Concentration 50
Molecular Structure
Neoplasms / genetics,  metabolism,  pathology
Nitroimidazoles / chemistry,  pharmacology*
Oxidation-Reduction / radiation effects
Oxygen / pharmacology
Phosphoramide Mustards / chemistry,  pharmacology*
Phosphorylation / drug effects
Prodrugs / chemistry,  pharmacology*
Spheroids, Cellular / drug effects*,  metabolism,  pathology
Tumor Stem Cell Assay
Grant Support
ID/Acronym/Agency:
P01 CA129186/CA/NCI NIH HHS; T32 GM007205/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/H2AFX protein, human; 0/Histones; 0/Nitroimidazoles; 0/Phosphoramide Mustards; 0/Prodrugs; 0/TH 302; S88TT14065/Oxygen

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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