Cyanoethylene oxide (CEO), a putative toxic and carcinogenic metabolite of acrylonitrile, is a direct-acting mutagen. The focus of this study was to elucidate potential adducts responsible for the mutagenic effect of CEO by characterizing products from the reaction of CEO with nucleotides. The reaction of CEO with the 5'-monophosphates of deoxyguanosine, deoxyadenosine, deoxycytidine or deoxythymidine resulted in the formation of at least one adduct for each nucleotide. Using two-dimensional NMR spectroscopy and fast atom bombardment mass spectrometry, CEO-nucleotide adducts (approximately 25% modification) were characterized as 2-cyano-2-hydroxyethyl phosphodiesters. The isolate from the reaction of deoxyguanosine-5'-monophosphate (dGMP) with CEO contained a second adduct, identified as N7-(2-cyano-2-hydroxyethyl)-dGMP. Single and double strand breaks, which were observed in supercoiled pBR322 plasmid DNA exposed to CEO (> 50 mM), may arise following formation of cyanohydroxyethyl phosphotriester adducts. The characterization of these phosphodiester adducts in vitro may provide insight into the intermediates responsible for the genotoxic effect of CEO in vivo.
Cyanoethylene oxide (CEO), the putative toxic and carcinogenic metabolite of acrylonitrile, is a direct-acting mutagen. CEO reacted with deoxythymidine (dT) to form a single adduct (approximately 3% dT modified). Using two-dimensional NMR spectroscopy and fast atom bombardment mass spectrometry, this adduct was identified as N3-(2-cyano-2-hydroxyethyl)deoxythymidine. Subsequently, degradation of the adduct yielded N3-(2,2-dihydroxyethyl)deoxythymidine, a hydrated form of N3-(oxoethyl)deoxythymidine. N3-(2-cyano-2-hydroxyethyl)deoxythymidine was also detected in the reaction of [2,3-14C]CEO with calf thymus DNA. Small UV peaks, not present in the control, were detected from the reaction of CEO with dA, dG and dC. However, neither their retention times nor spectral characteristics corresponded with the standards used in this study. Characterization of this cyano-hydroxyethyl adduct and its degradation product following in vitro exposure of nucleosides to CEO may provide insight as to the types of adducts that could be assessed as biomarkers in vivo, and the modifications responsible for the mutational effects of CEO.
Background
The local-regional failure of advanced oral squamous cell carcinoma (OSCC) after surgery results from the re-growth of residual tumor cells that may be stimulated by epidermal growth factor receptor (EGFR) ligands during the wound-healing process.
Methods
The level of EGFR ligands in human drain fluids from OSCC resection and remote flap donor site were determined. A mouse model of microscopic residual OSCC was established and treated with cetuximab to measure tumor growth, survival, and cervical lymph node metastases. A mouse model of wound-healing was also established to assess the effect of an EGFR antibody on the wound-healing process.
Results
EGFR ligands are found in sites from OSCC resection. EGFR targeted therapy can delay tumor re-growth in a microscopic residual disease model of OSCC without significant effects on local wound-healing.
Conclusion
These results provide a strong rationale for clinical evaluation of this approach to treat patients with local-regionally advanced OSCC.
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