Azoxymethane-induced rat aberrant crypt foci: Relevance in studying chemoprevention of colon cancer

Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, C218 Banting Building, Postal Locator 2202D, Ottawa, K1A 0L2, Ontario, Canada.
World Journal of Gastroenterology (Impact Factor: 2.43). 12/2008; 14(43):6632-5. DOI: 10.3748/wjg.14.6632
Source: PubMed

ABSTRACT The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries. Aberrant crypt foci (ACF) represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans. ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis. For over two decades, since its first discovery, azoxymethane (AOM)-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens. Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system. There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up, and extensive research in this field is currently in progress. In chemoprevention studies, AOM-induced rat ACF have been very successful as biomarkers, and have provided several standardized analyses of data. There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome, however, and hence there has been an ambiguity about their role as biomarkers. The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies. The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.

  • Source
    • "Although ACF incidence is related to colon carcinogenesis, these preneoplastic lesions are heterogeneous and have different molecular characteristics (Raju, 2008). Thus, ACF with 1, 2 or 3 crypts per focus may regress over time, and those with greater multiplicity (ACF ≥ 4 crypts) may progress to form colon neoplasia and are therefore considered more aggressive (Magnuson et al., 1993; Perše and Cerar, 2011; Raju, 2008). In the present study, TB treatment reduced the ACF ≥ 4 crypts, suggesting that TB acts on more aggressive, aberrant crypt foci and reinforcing its role as an important chemopreventive agent in colon carcinogenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200 mg/100 g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100 g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week. After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p < 0.05) as well as the ACF with ≥ 4 crypts (p < 0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p < 0.05) and reduced DNA damage (p < 0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p < 0.05). TB administration resulted in increased colonic tissue concentrations of BA (p < 0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB.
    Toxicology and Applied Pharmacology 04/2014; DOI:10.1016/j.taap.2014.02.004 · 3.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: form only given. Aliphatic phenylene vinylene co-polymers are produced through condensation of dialdehydes and bis-phosphoranes (Wittig method). The aliphatic linker group is incorporated in the backbone of poly(phenylenevinylene) [PPV] chains by introducing a non-conjugated dialdehyde or bis-phosphorane into the PPV polymerization reaction [terephthalaldehyde + 1,4-xylylidene-bis-(triphenylphosphorane)]. By controlling co-monomer feed percentage of the linker group to influence conjugation length of the PPV segments, luminescence of the co-polymers can be varied from blue to green-yellow. The nature of the linker group affects material properties such as solubility and liquid crystallinity. A single-pot reaction methodology - utilizing chemicals commercially available -- is described. The length and amount of linker groups in the PPV-type polymers are systematically varied to produce a series of materials ranging from aliphatic flexible polymers to aromatic rigid polymers.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This review gives a comprehensive overview of cancer development and links it to the current understanding of tumorigenesis and malignant progression in colorectal cancer. The focus is on human and murine colorectal carcinogenesis and the histogenesis of this malignant disorder. A summary of a model of colitis-associated colon tumorigenesis (an AOM/DSS model) will also be presented. The earliest phases of colorectal oncogenesis occur in the normal mucosa, with a disorder of cell replication. The large majority of colorectal malignancies develop from an adenomatous polyp (adenoma). These can be defined as well-demarcated masses of epithelial dysplasia, with uncontrolled crypt cell proliferation. When neoplastic cells pass through the muscularis mucosa and infiltrate the submucosa, they are malignant. Carcinomas usually originate from pre-existing adenomas, but this does not imply that all polyps undergo malignant changes and does not exclude de novo oncogenesis. Besides adenomas, there are other types of pre-neoplasia, which include hyperplastic polyps, serrated adenomas, flat adenomas and dysplasia that occurs in the inflamed colon in associated with inflammatory bowel disease. Colorectal neoplasms cover a wide range of pre-malignant and malignant lesions, many of which can easily be removed during endoscopy if they are small. Colorectal neoplasms and/or pre-neoplasms can be prevented by interfering with the various steps of oncogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas and eventually evolves into malignancy. The knowledge described herein will help to reduce and prevent this malignancy, which is one of the most frequent neoplasms in some Western and developed countries.
    Journal of Carcinogenesis 02/2009; 8(1):5. DOI:10.4103/1477-3163.49014
Show more


Available from