Development of a liquid chromatography-electrospray ionization tandem mass spectrometry method for detecting oxaliplatin-DNA intrastrand cross-links in biological samples.
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AuthorsLe Pla, Rachel C.
Ritchie, Kenneth J.
Henderson, Colin J.
Wolf, C. Roland
Harrington, Chris F.
Farmer, Peter B.
MetadataShow full item record
AbstractCellular resistance, both intrinsic and acquired, poses a problem in the effectiveness of platinum-based chemotherapy. The cytotoxic activity of Pt-based chemotherapeutic agents is derived from their ability to react with cellular DNA. Oxaliplatin binds to the N7 position of the purine DNA bases, forming mainly intrastrand cross-links between either two adjacent guanines (GG), an adjacent adenine and guanine (AG), or two guanines separated by an unmodified nucleotide (GNG). We report the development of a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method for measuring GG and AG intrastrand cross-links formed by oxaliplatin. The limits of detection for GG-oxPt and AG-oxPt were 23 and 19 adducts per 10 (8) nucleotides, respectively. We compare the formation and persistence of intrastrand cross-links between wild-type and glutathione transferase P null mice (GSTP null) treated with oxaliplatin. No significant difference was observed in the level of intrastrand cross-links formed by oxaliplatin between the mouse strains in liver, kidney, and lung DNA. Adduct levels were greatest in liver and lowest in lung tissue.
CitationChem. Res. Toxicol. 2007, 20 (8):1177-1182
JournalChemical Research in Toxicology
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