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Title: The effects of potential chemopreventive agents on colorectal cancer : a novel approach in a murine model
Author: Bradley, Clare Josephine
ISNI:       0000 0004 2741 0106
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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This study investigates overexpression of the cytoplasmic protein metallothionein (MT) as a marker of precancerous change within the murine colon by immunohistochemistry and as a method for assessing the chemopreventive potential of chemical agents. It was found that the carcinogen azoxymethane (AOM) induced crypt-restricted MT overexpression in the colon of Balb/c mice and that the putative chemopreventive agents sulindac and genistein significantly inhibited AOM-induced MT overexpression in the colonic crypts but not the incidence of aberrant crypt foci (ACF). an extensively used prognostic indicator of CRC development. In spite of this, crypt-restricted MT overexpression correlated with the incidence of ACF. MT overexpression is heritable and clonal with mutated daughter cells progressively repopulating the crypt suggesting that MT overexpression denotes crypt stem cell mutation. Further investigation using a DNA fragmentation assay and β-catenin immunohistochemistry revealed that treatment with AOM significantly reduced the incidence of apoptosis and, although not significantly higher than control animals, showed nuclear localisation of β- catenin in colonic epithelial cells. Sulindac and genistein treatment had no significant effect on the incidence of apoptosis or nuclear expression of β-catenin within the colonic crypts of AOM-exposed mice. The current study suggests that crypt-restricted MT overexpression, although not implicated in the classical pathway of colorectal tumourigenesis, has potential to be used in pre-clinical animal studies as a surrogate reporter of mutations in key genes that are undetectable at the protein expression level in early stage tumour development. MT overexpression may also prove useful in pre- clinical assessment of the chemopreventive potential of drugs and dietary agents.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available