Document Detail


Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302.
MedLine Citation:
PMID:  22147748     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard currently undergoing clinical evaluation. Here we describe TH-302 broad spectrum activity, hypoxia-selective activation, and mechanism of action. The concentration x time (CT) dependence of TH-302 activation was examined as a function of oxygen concentration, with reference to the prototypic HAP tirapazamine, and demonstrated 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 gammaH2AX phosphorylation, DNA-cross-linking and cell cycle arrest. We utilized CHO 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 TH302 activity in the three dimensional tumor spheroid and multicellular layer (MCL) models. TH-302 showed much enhanced potency in H460 spheroids compared to H460 monolayer cells under normoxia. MCLs comprised of mixtures of parental HCT116 cells and HCT116 cells engineered to express an oxygen-insensitive bacterial nitroreductase demonstrated 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
Related Documents :
3021388 - Superoxide generation by pig alveolar macrophages.
9489998 - Effect of indomethacin on cell cycle dependent cyclic amp fluxes in tobacco by-2 cells.
6250538 - Consequences of hormone-induced desensitization of adenylate cyclase in intact cells.
10528228 - Keratinocyte growth factor accelerates wound closure in airway epithelium during cyclic...
7544358 - Evidence for the presence of a hg-inhibitable water-permeability pathway and aquaporin ...
10321688 - Mad-overexpression down regulates the malignant growth and p53 mediated apoptosis in hu...
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-6
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  -     ISSN:  1538-8514     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1Discovery, Threshold Pharmaceuticals.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

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


Previous Document:  Therapeutic Mechanism and Efficacy of the Antibody Drug-Conjugate BAY 79-4620 Targeting Human Carbon...
Next Document:  Trends and inequalities in late-life health and functioning in England.