Abstract | PURPOSE: EXPERIMENTAL DESIGN: Aerobic and hypoxic covalent binding of [(14)C]-EF5 was determined in human tumor cell lines, including lines with overexpression of NADPH:cytochrome P450 oxidoreductase (CYPOR), and reductive metabolism of tirapazamine and CEN-209 by mass spectrometry. DNA damage response was measured by γH2AX formation. Bioreductive metabolism was modulated in HCT116 tumor xenografts by overexpression of CYPOR and breathing of hyperbaric oxygen or 10% oxygen. RESULTS: Overexpression of CYPOR induced similar 2- to 4-fold increases in EF5 binding and metabolic reduction of tirapazamine and CEN-209 in SiHa and HCT116 cell lines, and similar enhancement of γH2AX formation. EF5 binding and metabolic reduction of the prodrugs were highly correlated in a panel of 14 hypoxic tumor cell lines. In HCT116 xenografts, CYPOR overexpression also significantly increased EF5 binding and CEN-209 reduction, and modification of tumor hypoxia caused similar changes to the bioreductive activation of both agents, resulting in a strong correlation between EF5 binding and CEN209-induced DNA damage (R(2) = 0.68, P < 0.0001) at the individual tumor level. CONCLUSIONS:
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Authors | Jingli Wang, Annika Foehrenbacher, Jiechuang Su, Rita Patel, Michael P Hay, Kevin O Hicks, William R Wilson |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 18
Issue 6
Pg. 1684-95
(Mar 15 2012)
ISSN: 1557-3265 [Electronic] United States |
PMID | 22167409
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 5-(2,2-dimethyl-1,3-propoxy cyclophosphoryl)-5-methyl-1-pyrroline N-oxide
- CETN2 protein, human
- Calcium-Binding Proteins
- Cell Cycle Proteins
- Cyclic N-Oxides
- H2AX protein, human
- Histones
- Hydrocarbons, Fluorinated
- Indicators and Reagents
- Prodrugs
- Triazines
- Tirapazamine
- Etanidazole
- 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide
- Oxidoreductases
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Topics |
- Animals
- Calcium-Binding Proteins
(metabolism)
- Cell Cycle Proteins
(metabolism)
- Cell Hypoxia
- Cell Line, Tumor
- Cyclic N-Oxides
(metabolism)
- Etanidazole
(analogs & derivatives, analysis, metabolism)
- Female
- HCT116 Cells
- Histones
(metabolism)
- Humans
- Hydrocarbons, Fluorinated
(analysis, metabolism)
- Indicators and Reagents
- Mice
- Oxidoreductases
(metabolism)
- Prodrugs
(pharmacology)
- Tirapazamine
- Transplantation, Heterologous
- Triazines
(metabolism)
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