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

Butyrate has induced differentiation in neoplastic cells grown in vitro, among them being colon cancer cell lines. In vivo, only one major study used sodium butyrate in the drinking water and showed an elevation in 1,2-dimethylhydrazine induced colon cancer in rats. Seeking to show that it was the sodium and not the butyrate which was responsible for the enhancement, we fed tributyrin at a 5% level to mice for 48 weeks. Mice experienced normal growth and development at this dose. Analysis of short chain fatty acids in the feces after 6 months in tributyrin feeding showed a 10-fold increase in butyric acid. However no difference in AOM induced focal areas of dysplasia or colonic tumor incidence was observed between tributyrin fed and control mice. At least two conclusions have been reached by this study, (1) that the dietary use of a sodium salt can contribute to the enhancement of chemically induced colon neoplasia and (2) butyrate may be discounted as providing any major therapeutic benefit against colonic tumorigenesis.
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PMID:Dietary butyrate (tributyrin) does not enhance AOM-induced colon tumorigenesis. 235 22

Animal models have been used extensively to study the role of diet in the etiology and prevention of colon cancer. It is recognized that several experimental variables affect disease modulation and outcome. Our objective was to determine whether an interaction between the dose of carcinogen used and dietary factors exist, using aberrant crypt foci (ACF) as a biological end point. Sprague-Dawley male rats were injected with a low or a high dose of azoxymethane (AOM, 5 mg or 20 mg per kg s.c.) or saline (0.2 ml/animal s.c.), and randomly allocated to four diet groups (N = 8/group) 1 week later. Diets varied with respect to type of fat (corn or olive oil) and levels of fat: normal (5 g/100 g) corn or olive oil (CO or OO), or high (23.5 g/100g) corn or olive oil (HCO or HOO). After 8 weeks of dietary treatment animals were injected with colchicine (1 mg/kg). Two and a half hours later they were killed and their colons assessed for number of ACF, number of crypt/focus (crypt multiplicity), and the size of ACF as well as the number of cells in metaphase and their location in the crypt section. The low dose of AOM induced fewer ACF and ACF with higher crypt multiplicity than did the high dose of AOM. Dietary fats exerted a variable effect on ACF, depending on the dose of AOM. In low-dose AOM groups, both CO diets exerted a growth-enhancing effect on ACF compared with OO diets.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Varying effect of dietary lipids and azoxymethane on early stages of colon carcinogenesis: enumeration of aberrant crypt foci and proliferative indices. 755 72

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

The typical high-fat, low-fiber American diet promotes colon cancer. An alternative to radical changes in dietary habits is to reinforce the diet with cancer protectors. Experiments to evaluate the effects of beta-carotene in the presence of high fat and low and high dietary levels of wheat bran fiber were designed using the Fischer-344 rat colon cancer model. Rats (20/group), were given either high fat (20% w/w), low wheat bran, fiber (1% w/w) diets, or high fat (20% w/w) high wheat bran fiber (8% w/w) diets, with different levels of beta-carotene. After 2 weeks of adaptation, half were given two weekly s.c. injections of azoxymethane (AOM, 15 mg/kg body wt); and half two weekly s.c. injections of saline. Six weeks later, five rats from each dietary group were killed to evaluate the comparative effect of different dietary regimens on the induction of colon aberrant crypt foci (ACF). The remaining rats were maintained on their respective diets for an additional 20 weeks to examine the effect on colon tumor incidence. The total number of ACF/rat in the low-fiber groups declined from 44.0 +/- 4.18 to 12.8 +/- 1.95 in response to increasing amounts of beta-carotene from 1 to 20 mg/kg diet. A similar progressive reduction in total ACF/rat was also seen in the high-fiber groups (20.8 +/- 2.92 to 9.2 +/- 0.58). ACF did not develop in the saline-exposed groups. Similarly colon tumor incidence declined from 73% to 20% in high-fiber groups and from 27% to 13% in low-fiber groups in response to increasing amounts beta-carotene from 1 to 20 mg/kg diet. The results showed that beta-carotene and wheat bran, individually and when combined, protected the colon in rats consuming high-fat, western-style diets from ACF and benign or malignant tumor formation.
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PMID:Effect of beta-carotene and wheat bran fiber on colonic aberrant crypt and tumor formation in rats exposed to azoxymethane and high dietary fat. 783 97

Aberrant crypt foci (ACF) consisting of one more single aberrant crypts (AC) are putative preneoplastic lesions that have been proposed as intermediate biomarkers for colon cancer. Using ACF as the end-point we have studied the effects of two different classes of colon carcinogens, 1,2-dimethylhydrazine dihydrochloride (DMH; 10 or 20 mg/kg body wt/injection) or its metabolite azoxymethane (AOM; 5 mg/kg) and 3,2'dimethyl-4- aminobiphenyl hydrochloride (DMAB; 50 mg/kg) in F344 and Lewis rats. Each carcinogen was given alone or DMH/AOM and DMAB were given in combination in either alternating or successive order in multiple doses. Each compound given alone induced ACF in both rat strains and the effect was most pronounced in the F344 rats. DMAB, not previously tested for ability to induce ACF in rats, was clearly less potent than DMH or AOM. The highest number of ACF was found distally in the colon, independent of treatment or rat strain. Surprisingly, DMAB markedly decreased the carcinogenic effect of DMH, evaluated both as numbers of ACF and AC per colon, as well as number of ACF with four or more AC, when both classes of carcinogens were given alternately. A more pronounced reduction was found in F344 rats than in Lewis rats, being 75-77% and 64-68% respectively with the highest DMH dose. The same tendency was found with successive exposure to DMAB followed by DMH or AOM. These differences in timing of exposure and the different metabolic pathways used by the two classes of carcinogens make a metabolic interaction unlikely as the reason for the antagonistic effect of DMAB on DMH or AOM. The type of standard diet used was found to influence the induction of ACF by the colon carcinogen DMH.
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PMID:Unexpected antagonistic action of 3,2'-dimethyl-4-aminobiphenyl on aberrant crypt induction by 1,2-dimethylhydrazine or azoxymethane in rat colon. 860 73

Colonic mucosal proliferation, aberrant crypt foci (ACF) induction, and fecal bile acids, parameters connected to the risk of colon cancer development, were studied in female F344 rats treated with starch or sucrose boluses or with a sucrose diet. Cell proliferation was higher in animals treated with a single sucrose bolus than in those given a starch bolus (15 g/kg body wt), with 4.3 +/- 0.64 and 2.17 +/- 0.57 (SE) mitotic figures (MF) per crypt in the sucrose and starch bolus groups, respectively (p < 0.01). When azoxymethane (AOM, 20 mg/kg) was administered 24 hours after a single sucrose or starch bolus, the number of ACF per colon after 30 days was higher in the sucrose bolus group [107.5 +/- 9.5 (SE)] than in the starch bolus group (67.8 +/- 0.9, p < 0.01). In additional experiments, colon cell proliferation (MF/crypt) was higher in rats given boluses of sucrose three times per week for 40 days after AOM (20 mg/kg) [5.9 +/- 0.7 (SE)] than in rats given starch boluses (2.96 +/- 0.4) or fed sucrose continuously (3.6 +/- 0.5). On the contrary, after 40 days of dietary treatment, the number, dimension, and percentage of ACF secreting sulfomucins and sialomucins were not varied among these three groups. However, the percentage of "large ACF" (ACF with > or = 4 crypts) secreting sialomucins or predominantly sialomucins was higher (p < 0.05) in the sucrose bolus group than in the starch group. The concentration of fecal bile acids and long-chain fatty acids was the same in the sucrose and starch groups, but the concentrations of deoxycholic and oleic acid were significantly higher in the sucrose bolus group. In conclusion, the administration of sucrose as a bolus had a stronger effect than continuous sucrose feeding on some parameters related to colon carcinogenesis and might be considered a risk factor in colon carcinogenesis.
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PMID:Effects of repeated boluses of sucrose on proliferation and on AOM-induced aberrant crypt foci in rat colon. 871 Jun 88

The role of dietary fiber in colon cancer is still not clear. Epidemiological studies suggest a protective role for high fiber intake. However the data suggest that the effects of fiber must be considered in the context of the total diet and its interactions with other dietary components. The typical Sonora diet is high in dietary fiber (7.8%) and the majority of this fiber (71%) is insoluble. Comparing the incidence of colon cancer in Sonora with its neighboring state of Arizona, in 1991, Sonora reported 40 cases of colon cancer, a population of 1,823,606, compared to 1432 for Arizona (3,763,322 inhabitants). The typical regional diet was evaluated for its protective effect in the development of colon cancer in rats injected with azoxymethane, AOM. The regional diet showed a tendency to protect against colon cancer, an incidence of 45% compared to 66% for the control diet, although this effect was not significant (p = 0.15). Further studies are needed to fully evaluate the diet and certain interactive dietary factors such as fat, quantity as well as type, protein, calcium and antioxidant nutrients.
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PMID:Colon cancer in rats and diet in the Sonoran desert region of Mexico. 916 57

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

Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin have been shown to suppress colon carcinogenesis and in some cases reduce the size of colorectal polyps. Balsalazide disodium (BSZ) is a colon-specific prodrug of the salicylate, 5-aminosalicylic acid. The aim of the present study was to test the chemopreventive activity of BSZ in two established animal models of colon tumorigenesis, azoxymethane-induced aberrant crypt formation in the rat and intestinal tumor formation in the B6-Min/+ mouse. Aberrant crypt foci (ACF) were induced in Fischer 344 rats via 2 subcutaneous injections of azoxymethane (20 mg/kg). BSZ was supplied in the drinking water for 8 weeks and ACF quantitated. B6-Min/+ mice were treated from 55 days of age for 90 days and intestinal tumors scored for number, size and location. BSZ treatment of AOM-injected rats reduced ACF formation in a dose-dependent manner by 60% with the greatest effect observed on ACF with 4 or more crypts. In B6-Min/+ mice a dose-dependent reduction of intestinal tumor number was observed which reached 80% in the distal small intestine and colon. A preliminary mechanistic study in cultured human colon cancer cells showed that both BSZ and 5-ASA inhibited colon cancer cell proliferation in vitro. However, 5-ASA but not BSZ produced changes consistent with the induction of apoptosis. BSZ produces a dose-dependent chemopreventive effect on colon carcinogenesis. A possible mechanism is consistent with the inhibition of cellular proliferation and the induction of apoptosis.
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PMID:Chemoprevention of colon cancer carcinogenesis by balsalazide: inhibition of azoxymethane-induced aberrant crypt formation in the rat colon and intestinal tumor formation in the B6-Min/+ mouse. 1085 36

The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced colon carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced colonic ACF, being putative precursor lesions for colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced colon carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. beta-Glucuronidase activity, PGE(2) level and polyamine content were decreased in colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human colon cancer.
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PMID:Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. 1221 75


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