N12008: Alkylated s-cysteine MGMT adducts as biomarkers of mutagenic agents in the colon
Wednesday 10 September 2003
This research project aims to identify mutagenic agents that can cause colorectal cancer and lead to a better understanding of dietary factors that determine susceptibility.
Background
Promoter methylation of the DNA repair protein, MGMT, is associated with K-ras GC~AT transition mutations in colorectal cancer implicating alkylating agent exposure as a key aetiological factor in this mutagenic event. As alkyl groups of Q6-alkylguanines are specifically transferred to a cysteine acceptor group (position 145) in MGMT, the measurement of these alkylated S-cysteine residues will provide a direct record of mutagen exposure.
Research Approach
In this pilot study, alkylated S-cysteine MGMT standards will be synthesised and adducts detected by mass spectroscopic analysis of intact MGMT and enzymatically released peptides. To demonstrate the feasibility of this approach alkylated S-cysteine residues will be measured in tissues obtained from animals treated with alkylating agents and from human colorectal tissues. This new approach will enable the rapid and cost-effective identification of those genotoxic agents that cause MGMT-repairable DNA alkylation and lead to a better understanding of dietary factors that determine colorectal cancer susceptibility.