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

Foci of aberrant crypts (ACF) have been identified in the unsectioned methylene blue stained rodent colons and hypothesized to represent precursor lesions of colon cancer. In the present study, induction and growth characteristics of ACF were investigated in response to a single injection of varying dosages of 1,2-dimethylhydrazine-2HCl (DMH), a colon carcinogen. Female Sprague-Dawley rats were given a single injection of DMH (5-150 mg/kg). Two and 19 weeks after the injection, animals were killed and their distal 10 cm of colons were enumerated for the number and crypt multiplicity of ACF. Number of ACF increased with increasing dosages of DMH plateauing at 100 mg/kg. However, percentage of ACF exhibiting different crypt multiplicity (1 to greater than 4) were similar among different dose groups. Aberrant crypts and normal crypts were enumerated for total number of cells and number and distribution of S-phase cells along the crypt height 19 weeks after DMH injection after autoradiography. The labeling index (LI) (percentage of S-phase cells) and LI along the crypt height were determined. Compared to the surrounding normal crypts, aberrant crypts exhibited significantly higher (P less than 0.05) number of cells (1122 +/- 81 versus 411 +/- 28) and higher (P less than 0.05) LI (21 +/- 1 versus 12 +/- 1). For the eight ACF analysed in the present study, the distribution of S-phase cells in the aberrant crypts were similar to that of normal crypts in that S-phase cells were restricted to the lower two-thirds of the crypts rather than distributed throughout the height of the crypts as reported for adenomatous epithelium.
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PMID:Dose response and proliferative characteristics of aberrant crypt foci: putative preneoplastic lesions in rat colon. 193 94

Carcinogen-treated rats develop foci of aberrant crypts in the colon (ACFs) that have been interpreted as preneoplastic lesions. To characterise ACFs further, we studied in the unsectioned colon of rats the number, multiplicity, some morphological characteristics and the type of mucin production in ACFs. In ACFs observed 115 days after the administration of 50 mg kg-1 1,2-dimethylhydrazine (DMH), crypt multiplicity [number of aberrant crypts (AC) per focus] was positively correlated (P < 0.0001) with the reduction of goblet cells, and with luminal and nuclear alterations in the cells surrounding the lumen of the ACs. We studied mucin production in the unsectioned colon, demonstrating that ACFs producing sulphomucins (like the normal distal rat colon) were progressively reduced when ACF multiplicity increased, whereas ACFs containing sialomucins (correlated with an increased risk of colon cancer) or both sulphomucins and sialomucins increased with crypt multiplicity. We also studied ACFs in the colon and the occurrence of intestinal tumours in rats treated with azoxymethane (AOM; 64 mg kg-1). A significant association was found (P = 0.04) between tumours and the presence of 'large' ACFs (AC/ACF > 14 crypts) and a borderline significant association (P = 0.057) between the presence of tumours and sialomucin-producing ACFs. We found no association between the number of ACFs, ACF multiplicity and the presence of tumours.
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PMID:Characterisation of aberrant crypt foci in carcinogen-treated rats: association with intestinal carcinogenesis. 771 Sep 42

Foci of aberrant crypts (ACF) have been observed on the unsectioned, methylene blue-stained mucosal surface of the human colon. Experimental evidence and the histological features of the lesions suggest that they might be early events in colon cancer development. The main objective of the present study was to evaluate cell kinetic properties of ACF in the human colon. Five samples of colon mucosa were collected immediately after operation following the administration of 500 mg of 5'-bromo-2'-deoxyuridine prior to surgery. ACF were then identified on the fixed, unsectioned, methylene blue-stained mucosal surface under a light microscope. Some specimens containing ACF were serially sectioned perpendicular to the luminal surface of the intestine, along with specimens of normal-appearing mucosa. Several sections were prepared for the immunohistochemical identification of 5'-bromo-2'-deoxyuridine-incorporating cells (in the S phase of the cell cycle). The results of this study demonstrated that aberrant crypts have more cells per crypt than normal glands. Total labeling index and labeling index values in each of the five longitudinal compartments in which each crypt was divided showed an increased total proliferative activity in all ACF examined, although limited to the lower crypt compartments in almost all aberrant crypts evaluated. These findings are in keeping with previous cell kinetic studies and observations in experimental animals and provide evidence of the involvement of human aberrant crypts in the stepwise process leading from normal mucosa to colon cancer.
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PMID:Cell kinetic evaluation of human colonic aberrant crypts. (Colorectal Cancer Study Group of the University of Modena and the Health Care District 16, Modena, Italy). 833 83

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces aberrant crypt foci (ACFs) as well as colon cancer in F344 male rats. Conditions allowing rapid development of ACFs over a short period were investigated. F344 male rats were fed 400 ppm of PhIP x HCl in a low-fat diet (LF) for 2 weeks and then given a PhIP-free, high-fat diet containing PRIMEX (HF-PR) or safflower oil, or PhIP-free LF for 4 or 12 weeks. Rats fed HF-PR for 4 weeks gave the highest number of ACFs/rat (3.3) and their size in terms of aberrant crypts/ACF (2.7) was much larger than that obtained with conventional continuous feeding of PhIP for 25 weeks in the CE-2 diet. Therefore, 2 weeks of dietary exposure to 400 ppm of PhIP x HCl, followed by HF-PR for 4 weeks, is a practical and convenient method for obtaining ACFs. This protocol should be useful for studies of the early phase of colon carcinogenesis.
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PMID:Efficient method for rapid induction of aberrant crypt foci in rats with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 895 59

Calcium has been proposed for prevention of colon cancer. The effects of calcium on azoxymethane (AOM)-induced aberrant crypt foci (ACP), a putative precancerous lesion, and cell proliferation were determined in rat colon. Male F344 rats were given AIN-76A diet that contained calcium at concentrations of 0.5, 1.0, 2.5, 5.0, 10.0 and 15.0 g/kg in experiment 1 and 0.2, 2.0 and 6.0 g/kg in experiment 2. One week after the rats received these diets, they were given the first of two weekly 15 mg/kg injections of AOM. The rats were killed after 35 days of exposure to the different diets. In experiment 1, exposure to either low (0.5 and 1.0 g/kg) or high (10.0 and 15.0 g/kg) concentrations of calcium reduced the yield of ACF relative to 5.0 g/kg calcium. In experiment 2, exposure to 0.2 and 2.0 g/kg calcium resulted in a lower yield of ACF than 6.0 g/kg. Cell proliferation in ACF and non-involved crypts was reduced in animals that received 0.5 or 15.0 mg/Kg relative to 5.0 mg/kg diet calcium. Our results indicate that both lower and higher concentrations of calcium relative to its standard concentration in AIN-76A diet can prevent ACF and reduce the extent of cell proliferation in the lesion which would likely lead to the prevention of colon cancer.
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PMID:Effect of calcium on azoxymethane-induced aberrant crypt foci and cell proliferation in the colon of rats. 950 Jan 89

Although the cyclooxygenase pathway of the arachidonic acid cascade has been suggested to play an important role in colon carcinogenesis, the molecular species of prostanoids and receptors involved have not been fully elucidated yet. We examined the development of aberrant crypt foci (ACFs), putative preneoplastic lesions of the colon, in two lines of knockout mice, each deficient in prostaglandin E receptors, EP1 and EP3, by treatment with the colon carcinogen, azoxymethane. Formation of ACFs was decreased only in the EP1-knockout mice to approximately 60% of the level in wild-type mice. Administration of 250, 500, or 1000 ppm of a novel selective EP1 antagonist, ONO-8711, in the diet to azoxymethane-treated C57BL/6J mice also resulted in a dose-dependent reduction of ACF formation. Moreover, when Min mice, having a nonsense mutation in the adenomatous polyposis coli gene, were given 500 ppm ONO-8711 in the diet, the number of intestinal polyps was significantly reduced to 57% of that in the basal diet group. These results strongly suggest that prostaglandin E2 contributes to colon carcinogenesis to some extent through its action at the EP1 receptor. Thus, EP1 antagonists may be good candidates as chemopreventive agents for colon cancer.
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PMID:Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. 1053 80

Dietary sphingomyelin (SM) inhibits early stages of colon cancer (appearance of aberrant crypt foci, ACF) and decreases the proportion of adenocarcinomas vs. adenomas in 1,2-dimethylhydrazine (DMH)-treated CF1 mice. To elucidate the structural specificity of this inhibition, the effects of the other major sphingolipids in milk (glycosphingolipids) were determined. Glucosylceramide (GluCer), lactosylceramide (LacCer) and ganglioside G(D3) were fed individually to DMH-treated (six doses of 30 mg/kg body weight) female CF1 mice at 0.025 or 0.1 g/100 g of the diet for 4 wk. All reduced the number of ACF by > 40% (P < 0.001), which is comparable to the reduction by SM in earlier studies. Immunohistochemical analysis of the colons revealed that sphingolipid feeding also reduced proliferation, with the most profound effect (up to 80%; P < 0.001) in the upper half of the crypts. Since the bioactive backbones of the glycosphingolipids (i.e., ceramide and other metabolites) are the likely mediators of these effects, the susceptibility of these complex sphingolipids to digestion in the colon was examined by incubating 500 microgram of each sphingolipid with colonic segments from mice and analysis of substrate disappearance and product formation by tandem mass spectrometry. All of the sphingolipids (including SM) disappeared over time with a substantial portion appearing as ceramide. Partially hydrolyzed intermediates (such as GluCer from LacCer or G(D3)) were not detected, which suggests that the cleavage involves colonic (or microflora) endoglycosidases. In summary, consumption of dairy SM and glycosphingolipids suppresses colonic cell proliferation and ACF formation in DMH-treated mice; hence, many categories of sphingolipids affect these key events in colon carcinogenesis.
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PMID:Colonic cell proliferation and aberrant crypt foci formation are inhibited by dairy glycosphingolipids in 1, 2-dimethylhydrazine-treated CF1 mice. 1070 79

The effect of the NSAIDs, retinoids and DFMO on AOM-induced colon tumors, and ACF, cell proliferation, and apoptosis is summarized in Table 1. The ability to prevent AOM-induced ACF has been used as an assay to screen agents for chemoprevention. As discussed above, all six potential chemopreventive agents, aspirin, 2-CPR, DFMO, 4-HPR, piroxicam, and 9-cis-retinoic acid, decreased the level of AOM-induced ACF. However, two of the agents, aspirin (at doses that greatly reduced the yield of ACF) and 2-CPR did not prevent AOM-induced colon tumors. Hence, aspirin and 2-CPR would appear to be false positive in the ACF assay. Besides being a false positive in the ACF assay, 2-CPR actually had the opposite effect of doubling the yield of colon tumor. The false positive result for aspirin could be due to the lower sensitivity of the AOM-induced colon cancer assay compared to the ACF assay. However, aspirin [table: see text] significantly reduced the yield of ACF at a dose (600 mg/kg diet) one-third the dose (1800 mg/kg diet) that did not reproducibly reduce the yield of colon tumors. Thus, although there were no false negative results, two of the six agents gave false positive results in the AOM-induced ACF assay with respect to their ability to prevent colon cancer. Two other potential biomarkers for chemopreventive activity are the ability to reduce the level of cell proliferation and to enhance the level of apoptosis. All six of the agents including aspirin and 2-CPR reduced the level of cell proliferation in adenomas. Thus, similar to their ability to prevent ACF, the ability of aspirin and 2-CPR to decrease cell proliferation were also false positive responses with respect to prevention of colon cancer, but not with respect to the prevention of ACF. Piroxicam, the most potent of the six agents in preventing AOM-induced colon cancer, did not significantly affect the level of cell proliferation in adenomas which is a false negative response. Hence, only three of the six agents (50%) were correctly identified as potential chemopreventive agents by their ability to reduce the level of cell proliferation. In contrast, retinoids, including the three discussed here, demonstrated good correlation between the ability to prevent AOM-induced ACF and the ability to decrease cell proliferation in colonic mucosa or ACF. Thus, within some classes of agents such as the retinoids, the ability to prevent ACF and to reduce cell proliferation appear to correlate, while in other classes including the NSAIDs, the correlation appeared not to exist. The four agents that prevented colon cancer all enhanced the level of apoptosis, while the two agents that did not prevent colon cancer did not effect apoptosis. Three other chemopreventive agents, including phenylethyl-3-methylcaffeate and the NSAIDs, curcumin and sulindac, have been shown by Samaha et al. to enhance apoptosis in AOM-induced colon tumors. Thus, although a very limited number of chemopreventive agents have been evaluated for the ability to enhance apoptosis in the colon, there appears to be an association between the ability to enhance apoptosis and the ability to prevent colon cancer. The use of the AOM-induced ACF assay to screen agents for the ability to prevent colon tumors would appear to result in false positive responses including agents (2-CPR and quercetin) that actually promote colon cancer. However, our results suggest that false positive responders could be distinguished by their inability to enhance apoptosis while potential chemopreventive agents would enhance it. It is therefore proposed that a Two Step Procedure be used to screen agents for the ability to prevent colon cancer. Step 1 would be the determination of the ability to prevent ACF. Because the ACF assay appears to suffer more from false positive than from false negative responders, apparently few potent chemopreventive agents would be missed. Also the ACF assay could be the source of foci for evaluation of the effect
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PMID:Prevention of colon cancer and modulation of aberrant crypt foci, cell proliferation, and apoptosis by retinoids and NSAIDs. 1070 74

Colon cancer is the third most common newly diagnosed cancer in the United States and the third most common cause of cancer-related deaths. Previous supplementation studies have demonstrated the efficacy of selenium (Se) for prevention of colon cancer in humans. The metabolism of Se depends on its chemical form, and studies have shown that the chemical form of Se in broccoli does not accumulate in the body as fast as other forms of Se and may be especially beneficial for prevention of cancer. In the first experiment of the present study, Fisher F-344 rats (n = 45) were allotted randomly to torula yeast-based diets supplemented with the following: 1) no Se; 2) 0.1 microg Se/g diet as selenate; 3) 1.0 microg Se/g diet as selenate; 4) 0.1 microg Se/g diet as selenized broccoli (Se concentration of approximately 500 microg/g); or 5) 1.0 microg Se/g diet as selenized broccoli. In Experiment 2, rats (n = 80) were allotted randomly to the same basal diet supplemented with the following: 1) no added Se; 2) 2.0 microg Se/g diet as selenite; 3) 2. 0 microg Se/g diet as selenite + low Se broccoli; and 4) 2.0 microg Se/g diet as selenized broccoli. Rats were fed the diets for 2 wk and injected with a chemical carcinogen (3,2 dimethyl 4-amino biphenyl or dimethyl-hydrazine in Experiment 1 or dimethyl hydrazine in Experiment 2; 2 rats/treatment were used as vehicle controls). Supranutritional amounts of Se supplied as high Se broccoli significantly decreased (P: < 0.05) the incidence of aberrant crypts (AC) and aberrant crypt foci (ACF; preneoplastic lesions indicative of colon cancer) compared with other dietary treatments. Diets were controlled for the presence or absence of broccoli and for the total amount of Se. The reduction in AC and ACF was a function of Se in high Se broccoli and not a result of broccoli alone or Se alone. Adequate dietary Se supplied as high Se broccoli did not accumulate in tissues or increase glutathione peroxidase activity as well as other forms and amounts of Se. Thus, Se from high Se broccoli may be metabolized in a manner that diverts much of the Se into a pool that provides protection against colon cancer.
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PMID:Selenium from high selenium broccoli protects rats from colon cancer. 1095 40

The reduction in incidence of chemically-induced colon cancer by foods high in selenium (Se) was investigated in Fisher-344 rats. The foods used were high-Se broccoli (produced in a greenhouse by addition of selenate to the media surrounding the plant roots) and a processed high-Se wheat product (made by milling high-Se wheat purchased from a seleniferous area). Weanling rats were fed diets containing different amounts of Se from these foods or from selenium salts (selenite and selenate). Early in the experiment the animals were injected with a chemical carcinogen. After 11 weeks on diets animals were killed and the colons examined for preneoplastic lesions (aberrant crypts foci, ACF). ACF were significantly reduced in animals fed supra-nutritional amounts of Se from broccoli, despite the finding that Se from broccoli was poorly bioavailable. Supra-nutritional amounts of Se from high-Se processed wheat also significantly reduced aberrant crypts (AC), although pure selenomethionine, (the predominant chemical form of Se in wheat), did not significantly reduce AC. These results emphasize the need to study Se in food forms, and not extrapolate from previous studies using pure chemical forms in cancer inhibition studies. They also demonstrate that foods with high Se bioavailability are not necessarily the most efficacious for cancer incidence reduction.
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PMID:Selenium (Se) from high-selenium broccoli is utilized differently than selenite, selenate and selenomethionine, but is more effective in inhibiting colon carcinogenesis. 1156 56


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