O6-alkylguanines · Characterisation and quantification of O6-alkylguanine DNA adducts derived from nitrosated amino acids: Risk factors in colorectal cancer.

The exposure of DNA to alkylating agents can produce base adducts such as O6-alkylguanines, that if not repaired, can lead to a variety of effects including toxicity, mutagenicity and cancer. Although exposure may be significant for certain individuals such as workers in the chemical industry and smokers, all individuals are exposed to alkylating agents from dietary components or that derive from reactive intermediates formed endogenously. For example, nitrosation of dietary amines, amino acids and their derivatives can produce reactive alkylating agents that can result in the formation of a variety of DNA base adducts. One such adduct, O6-carboxymethylguanine (O6-CMG) has been directly correlated to dietary levels of red meat, a known risk factor for developing colorectal cancer, the second most common cancer in Europe. This proposal will use novel synthetic oligodeoxyribonucleotide (ODN) and nucleoside standards to develop highly sensitive mass spectrometry-based analytical methods to identify and quantify levels of specific O6-alkylguanine adducts in DNA. This methodology will enable links to be made between exposure and cancer risk, lead to the identification of novel predictive biomarkers and benefit the assessment of human health at both the individual and population level, paving the way for more informative monitoring studies.