title: Is the tissue persistence of O(6)-methyl-2'-deoxyguanosine an indicator of tumour formation in the gastrointestinal tract?
abstract: Azoxymethane (AOM) is a methylating agent capable of inducing mutations in DNA by forming adducts with DNA bases. It has been used to understand the mechanisms involved in colon carcinogenesis. Of the adducts formed in response to AOM, O(6)-methyl-2'-deoxy-guanosine (O(6)-mdGua) is the most mutagenic. Based on studies in rodents of the abundance and persistence of DNA adducts in various tissues after treatment with alkylating agents, previous results suggest, as a generalization, that the longer O(6)-mdGua adducts remain unrepaired in the cells of a tissue, the greater the risk for tumorigenesis. To test this hypothesis, we have built on these studies, expanding the number of tissues in which O(6)-mdGua abundance and persistence were examined and correlating these data with tumour distribution and abundance in rats maintained for 26 weeks after the treatment with AOM. Our study revealed firstly the existence of groups of tissues that developed relatively large amounts (proximal and distal colon, proximal small intestine (SI), liver and kidney) and relatively low levels (stomach, distal SI, bladder, spleen, blood and lung) of O(6)-mdGua after AOM exposure. Secondly, while all tissues showed an increase in adduct levels at 6h after mutagen treatment and most showed a significant drop in adduct levels between 6h and 48h (stomach, proximal and distal SI, liver, spleen, blood and lung), one group of tissues displayed O(6)-mdGua levels that did not decrease at 48h (proximal and distal colon, kidney and bladder). Predictably, the colon displayed tumours 26 weeks after treatment. Interestingly, however, the proximal SI also displayed significant tumour formation at that time. Our findings demonstrate (1) a direct association between exposure to O(6)-mdGua and tumours of the distal colon and (2) a dissociation of the relationship between adduct clearance and tumorigenesis in the SI. This diversity of response in the gastrointestinal tract warrants further analysis.
authors.affiliation: CSIRO Preventative Health National Research Flagship, Adelaide, SA 5001, Australia.
authors.forename: Shir Ley
authors.initials: SL
authors.lastname: Tan
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Gerber
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Cosgrove
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Lockett
authors.forename: Julie M
authors.initials: JM
authors.lastname: Clarke
authors.forename: Desmond B
authors.initials: DB
authors.lastname: Williams
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Head
mesh_terms: D000477:Alkylating Agents / Q000378:metabolism; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D003110:Colonic Neoplasms / Q000139:chemically induced*; D018736:DNA Adducts / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000139:chemically induced; D007421:Intestine, Small; D008297:Male; D008745:Methylation; D009153:Mutagens / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000477:Alkylating Agents; D018736:DNA Adducts; D009153:Mutagens; C015558:O(6)-methyl-2'-deoxyguanosine; D003849:Deoxyguanosine; D001397:Azoxymethane