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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aberrant crypt foci can be identified in the colons of rodents treated 3 wk earlier with azoxymethane, a known colon carcinogen. These crypts can easily be visualized in the unsectioned methylene blue-stained colons under light microscopy, where they are distinguished by their increased size, more prominent epithelial cells, and pericryptal space. They occur as single aberrant crypts or as two, three, or four aberrant crypts in a cluster. We compared the reported ability of carcinogens associated with the human diet to induce colon cancer with the measured rate of induction of aberrant crypts in female CF1 mice and Sprague-Dawley rats. The carcinogens used were 1,2-dimethylhydrazine, methyl nitrosourea, N-nitrosodimethylamine, benzo(a)pyrene, aflatoxin B1, 2-amino-6-methyldipyrido[1,2-alpha:3',2'-d]imidazole, 2-amino-3-methylimidazo[4,5-P]quinoline, 2-amino-3,4-dimethylimidazo[4,5-P]quinoline, and 3-amino-1-methyl-5H-pyrido[4,3-b]indole. Graded doses of these compounds were given to the animals by gavage twice with a 4-day interval, and the animals were terminated 3 wk later. All colon carcinogens induced aberrant crypts in a dose-related fashion. N-Nitrosodimethylamine and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, carcinogenic compounds that do not induce colon cancer, did not induce them. The ability of the studied compounds to induce aberrant crypts was species specific; e.g., aflatoxin B1 and 2-amino-3,4-dimethylimidazo[4,5-P]quinoline induce about 20 times more in rats than mice. This relationship was consistent with their reported ability to induce colon cancer in these species. Results of the present study support the use of the aberrant crypt assays to screen colon-specific carcinogens and to study the process of colon carcinogenesis.
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PMID:Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods. 291 53

The concept that diet plays an important role in the initiation and/or development of various types of tumors in man and experimental animals is well documented. The etiology of colon cancer is complex and multifactorial in nature, and there is little information on the dietary components that may act as initiators during colon tumorigenesis. We have evaluated various dietary heterocyclic mutagenic amines present in a typical "Western" diet for their nuclear damaging effect (presumably a genotoxic response) on the colonic epithelium of C57BL/6J mice in vivo. Among the mutagenic amines studied 2-amino-3,4-dimethylimidazo(4,5-f)quinoline and 2-amino-3-methylimidazo(4,5-f)quinoline were very potent inducers of nuclear aberrations. These observations provide us with clues that our daily diet may contain colon-specific genotoxic components. Promotional effects of dietary fat and/or bile acids on colon tumorigenesis have been well studied. Dietary levels of calcium (0.1, 0.5 or 1.0% by weight) appear to modify the toxicity of orally administered fat or cholic acid (assessed by quantifying cell proliferation). The colons of animals consuming 0.1% or 0.5% calcium diet were more susceptible to the toxicity, whereas the colons of those consuming a 1.0% calcium diet appeared more like control colons. These studies demonstrate a profound effect of dietary constituents on the pathobiology of the colonic epithelium which may have a marked influence on the colon tumorigenesis.
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PMID:Effect of dietary components on the pathobiology of colonic epithelium: possible relationship with colon tumorigenesis. 371 47

The diet contains various mutagens and carcinogens that can be classified into three groups: naturally occurring chemicals, synthetic compounds and compounds produced by cooking. The first group includes mycotoxins and plant alkaloids while the second is exemplified by food additives and pesticides. The third includes polycyclic aromatic hydrocarbons and heterocyclic amines (HCAs). HCAs are mutagenic to microbes and eukaryotes and their precursors are creatine or creatinine, sugars, and amino acids in meat and fish. Among 10 HCAs so far examined for carcinogenicity in rodents, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced colon cancer in rats. PhIP is an especially interesting compound inducing colon tumors specifically in male F344 rats and only very rarely in females, which develop mammary carcinomas at high frequency instead. Since induced DNA adduct levels, determined by the 32P-postlabeling method, were found to be almost the same in male and female F344 rats adduct formation in itself is not directly responsible for carcinogenesis. We established, however, that PhIP causes increased cell proliferation in colon mucosa but not in the non-target liver or kidney of male rats. Induction of cell proliferation is therefore possibly an additional important factor determining carcinogenic organ specificity. In terms of molecular alteration ras family gene mutations are very rare and no mutations are evident in the p53 gene in colon tumors induced by HCAs. Their development due to HCAs can thus be considered an appropriate experimental model for human colon tumors in which ras or p53 gene activation is not involved. Since HCAs are genotoxic compounds, a causal role in some stage of human colon carcinogenesis is plausible. Exposure to HCAs should accordingly be avoided as far as possible.
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PMID:Carcinogenic factors in food with relevance to colon cancer development. 769 98

Although dietary fibre is generally thought to protect against the development of colorectal cancer, some of the results of animal and epidemiological studies are equivocal. We believe that this may be because the term dietary fibre covers a range of complex materials and some may protect but others may not. Dietary fibre is mainly composed of plant cell walls which vary in composition and properties according cell type and plant species. In addition to polysaccharides, the walls of some plant cell types contain the hydrophobic polymers lignin or suberin. Two groups of mechanisms have been proposed for the way dietary fibres may protect against colorectal cancer: those in which the dietary fibre may act directly and those in which the dietary fibre may have an indirect effect as a consequence of it being degraded by colonic bacterial enzymes and the products fermented. Direct mechanisms include the adsorption of carcinogens onto undegraded dietary fibres which pass out of the intestinal tract in the faeces. we have shown that different types of plant cell walls adsorbed a range of carcinogens, including heterocyclic aromatic amines, to different extents. Cell walls that contained lignin or suberin adsorbed hydrophobic carcinogens particularly well. Furthermore, the presence of lignin, and probably suberin, in the walls makes them resistant to degradation in the colon. Wheat bran, which is a good source of dietary fibre, contains some cell types with lignified walls. We used Fischer-344 rats to test the ability of wheat bran to protect against the formation of aberrant crypts (which are considered to be precursors to colon cancer) caused by the heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Our results indicate that wheat bran protects and probably does so by a direct mechanism.
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PMID:Studies on the role of specific dietary fibres in protection against colorectal cancer. 865 79

The aberrant crypt foci (ACF) bioassay has been used extensively to study the early effects of different dietary components on the colonic mucosa of laboratory rodents. ACF are proposed to represent preneoplastic lesions of colon cancer. Compared to the normally used initiators 1,2-dimethylhydrazine dihydrochloride (DMH) and azoxymethane (AOM), the use of a diet-related colon cancer initiator, such as the heterocyclic amine 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) formed during meat cooking, would probably give a more relevant insight into diet-related colon carcinogenesis. In the present study it is shown that a feeding regimen with continuous low IQ doses (0.03% in the diet) throughout a study period of 10 weeks has a significant effect on the induction of ACF in the colon of male F344 rats. In addition, the study illustrates that the incidence of the IQ-induced ACF can be modulated by the amount of refined carbohydrates in the diet. Rats given a high sucrose/dextrin diet showed a significantly higher number of ACF compared to rats given a diet high in starches. The effect on tumor outcome will await the termination of a ongoing parallel study.
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PMID:Refined carbohydrate enhancement of aberrant crypt foci (ACF) in rat colon induced by the food-borne carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ). 869 37

Aberrant crypt foci (ACF) have recently been identified as early putative preneoplastic lesions which appear in the colons of experimental animals treated with colon carcinogens. In a recent study the two heterocyclic amines, 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) were shown to be able to induce ACF in the colon of mice after, respectively, 4 and 10 weeks of exposure. In spite of the induction of ACF in colon of mice, IQ and PhIP have not been found to have colon as target organ in carcinogenicity studies. Therefore, one may question that ACF induced by IQ and PhIP in mice represent early stages of colon cancer. In order to investigate the possible role of PhIP- and IQ-induced aberrant crypt foci in the development of colon cancer in mice, colons from mice participating in other IQ- and PhIP-studies of much longer duration were analyzed for ACF. The results of these studies showed that the number of ACF increased statistically significantly over time, and that the small ACF were predominant (95-100%) at all time-points. In conclusion, this finding suggests that the detection of a high number of ACF with low crypt multiplicity (1-3 AC/Focus) in mice colon after IQ- or PhIP-treatment is not indicative for the end-point colon cancer, and thus supports the hypothesis that only the presence of a high number of ACF with high crypt multiplicity is predictive for tumor outcome.
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PMID:The role of aberrant crypt foci induced by the two heterocyclic amines 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) in the development of colon cancer in mice. 901

Formulated diets associated with a high risk (HR) or low risk (LR) for colon cancer were used to assess the effect of diet on putative metabolic biomarkers in human flora-associated rats: The HR diet was high in fat and sucrose and low in calcium and fiber; the LR diet was low in fat and high in starch, calcium, and fiber. The nutrient-to-energy ratio and energy intake were the same for both diets. Body and liver weights were significantly higher in animals fed the HR diet, possibly due to greater energy availability from fat. Cecal weights were significantly higher in animals fed the LR diet, presumably due to a bulking effect of the fiber and increased bacterial biomass. The HR diet significantly altered cecal bacterial enzyme activity: beta-glucuronidase activity increased 2.5-fold, and beta-glucosidase activity was halved. Ammonia production and the bacterial metabolism of 2-amino-3-methyl-7H-imidazo[4,5-f] quinoline (IQ) to 7-hydroxy-IQ (7OHIQ) were significantly higher in animals fed the HR diet. The HR diet, which contained factors common to diets consumed throughout the Western world, increased beta-glucuronidase activity, elevated cecal ammonia concentrations, and enhanced the genotoxic risk from 7OHIQ formation, three putative metabolic biomarkers of colorectal cancer. The significance of the reduction in beta-glucosidase is unclear.
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PMID:Effects of high- and low-risk diets on gut microflora-associated biomarkers of colon cancer in human flora-associated rats. 910 54

The aberrant crypt foci assay has been used extensively to study different compounds for chemopreventive action, but almost all investigations have used initiators not normally found in the diet. In the present study two food-borne initiators, 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) were used. To simulate the human exposure further, we chose a feeding regimen with continuous low IQ- and PhIP-doses. Throughout the study female mice were given diets with or without 0.03% IQ or 0.03% PhIP. Two additional groups were given azoxymethane (AOM) (5 mg/kg body weight) and 1,2-dimethylhydrazine dihydrochloride (DMH-2HCl) (20 mg/kg body weight), respectively, one dose a week for two weeks. Animals were killed after four and 10 weeks. After four weeks only the mice dosed with IQ and PhIP had aberrant crypt foci. A much higher number of aberrant crypt foci were found in the IQ mice (31.8 +/- 5.2) than in the PhIP mice (0.5 +/- 0.3). After 10 weeks aberrant crypt foci were found in all dosed groups. The IQ mice had significantly more (P < or = 0.001) small and total aberrant crypt foci than the other groups. AOM and DMH induced a higher percentage of medium or large sized aberrant crypt foci than PhIP or IQ. The interpretation of the aberrant crypt foci as precursor lesions for colon cancer in the PhIP and IQ mice is difficult because PhIP and IQ have not been reported to be colonic carcinogens. If cooked food mutagens such as IQ or PhIP are to be used as initiators in the aberrant crypt foci test, the use of rats may be preferable.
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PMID:The ability of two cooked food mutagens to induce aberrant crypt foci in mice. 916 13

In order to increase the understanding of the factors responsible for causing human colon cancer, a technique was developed to detect genotoxic effects of chemicals in human colon cells. Risk factors suspected to be associated with the aetiology of human colon cancer were subsequently investigated: the method is based on the measurement of DNA damage in primary cells freshly isolated from human colon biopsies with the single cell microgel ectrophoresis technique ('Comet Assay'). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3-methyl-3H-imidazo[4,5f]quinoline (IQ), N-methyl-N-nitro-N-nitrosoguanidine (MNNG), dinitrosocaffeidine (DNC) lithocholic acid (LCA), hydrogen peroxide (H2O2) and benzo[a]pyrene (B[a]P) were investigated for their genotoxic and cytotoxic effects following 30 min incubation with colon cells of human, and for comparative purposes also of the rat colon. The nitrosamides (MNNG, DNC) were very genotoxic in human colon cells. MNNG was more genotoxic in human than in rat colon cells. In contrast, the rat colon carcinogens PhIP and IQ were not genotoxic in human colon cells. PhIP did induce DNA damage in rat colon cells, which correlates to its capacity of inducing tumors in this animal tissue. LCA was toxic (rat > human) and concomitantly caused DNA damage in higher concentrations. The widespread contaminant B[a]P was not genotoxic in colon cells of either species using this system. H2O2 was found to be a potent genotoxic agent to both rat and human colon cells (human > rat). In summary, those compounds chosen as representatives of endogenously formed risk factors (MNNG, H2O2, LCA) have a higher toxic and/or genotoxic potency in human colon tissue than in rat colon. They are also more effective in this system than the contaminants tested so far (B[a]P, PhIP, IQ). The newly developed technique is rapid and yields relevant results. It is a novel and useful approach to assess different chemical compounds for genotoxic activities in tumour target tissues of the human.
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PMID:Induction of DNA damage by risk factors of colon cancer in human colon cells derived from biopsies. 920 21

Clarification of the mutational fingerprints of HCAs offers a promising approach in the investigation of the role of heterocyclic amines (HCAs) in human carcinogenesis. We analyzed mutations in the tumor related genes of tumors induced by HCAs, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which mainly yield DNA-adducts of C8-guanine. The G-->T transversion at codon 13-2nd position in Ha-ras was predominantly observed in mouse forestomach and rat Zymbal gland tumors induced by MeIQ. In contrast, various types of mutation were detected in the ras family genes of rat Zymbal gland tumors induced by IQ; the presence of a methyl group at position 4 of imidazo[4,5-f]quinoline gave rise to a remarkable difference in the mutational fingerprint. Apc mutations were detected in PhIP- and IQ-induced rat colon tumors, with incidences of 50% (4/8) and 15% (2/13), respectively. All five mutations detected in the four PhIP-induced tumors consisted of a guanine deletion from the 5'-GGGA-3' sequence, in contrast with T to C and C to T mutations in IQ-induced tumors. Four of these five mutations shared seven common nucleotides, -GTGGGAT- surrounding the guanine; indicating that PhIP leaves a characteristic mutational fingerprint in Apc. Colon tumors induced by PhIP were also found to have mutations in their microsatellite sequences, and similar results were detected in mammary gland tumors induced by PhIP, contrasting with no mutations in IQ-induced colon tumors and a very low frequency of mutations in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Although the mechanisms involved in the induction of microsatellite mutations are not known yet, microsatellite mutations which can also be detected in sporadic human tumors, including colon and breast tumors, were indicated to be a characteristic of PhIP. Mammary tumors induced by PhIP showed loss of heterozygocity (LOH) at the distal part of chromosome 10, which shows synteny with the distal part of human chromosome 17, where LOH frequently occurs in human breast cancer. In conclusion, each heterocyclic amine leave a mutational fingerprint which is specific to each compound. Since the tumor-related genes involved in PhIP-induced tumors have characteristics in common with those in human cancers, further detailed analysis will provide us with useful information on mutational fingerprints, and on the possible contribution of PhIP to human colon cancer.
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PMID:Genetic changes induced by heterocyclic amines. 920 52


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