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PubMed2001

High susceptibility of Scid mice to colon carcinogenesis induced by azoxymethane indicates a possible caretaker role for DNA-dependent protein kinase.

Severe combined immunodeficiency (Scid) mice have defects in V(D)J recombination and DNA double-strand breaks repair caused by an inherited genetic defect in the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Scid mice are highly susceptible to development of T-cell lymphomas, and because of the nature of its association with DNA repair and recombination, DNA-PKcs is considered to belong to the caretaker class of tumor suppressor genes. In the present study, the susceptibility of Scid mice to colon carcinogenesis due to administration of azoxymethane (AOM) was investigated. Significantly higher susceptibility in terms of induction of both aberrant crypt foci (ACFs), putative pre-cancerous lesions of the colon and colon cancers was observed as compared with the isogenic strain, C.B-17 mice. The incidences of colon tumors, either adenomas or adenocarcinomas, in Scid and C.B-17 mice after administration of AOM (10 mg/kg body weight/week) for 6 weeks were 87% (26 of 30) and 50% (15 of 30), respectively, by experimental week 22 (P < 0.01). The multiplicity of colon tumors in Scid mice was also significantly higher than in C.B-17 mice, being 2.2 +/- 1.5 and 0.9 +/- 1.2, respectively (P < 0.001). The present study clearly demonstrated high susceptibility of Scid mice to colon carcinogenesis, which might be attributable to disruption of the caretaker role of DNA-PK in colonic epithelial cells.

Adenocarcinoma↗
PubMed2002

Antitumorigenic activity of the prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis on azoxymethane-induced colon carcinogenesis in rats.

Prebiotics such as fructans, and probiotics such as Lactobacilli or Bifidobacteria, or a combination of prebiotics and probiotics (synbiotics) are thought to be protective against colon cancer. Therefore, we studied whether the prebiotic inulin enriched with oligofructose (Raftilose-Synergy1, briefly, Synergy1, 10% of the diet), probiotics [Bifidobacterium lactis (Bb12) and Lactobacillus rhamnosus (LGG), each at 5x10(8) c.f.u./g diet] or synbiotics (a combination of the two) protect rats against azoxymethane (AOM)-induced colon cancer. Male F344 rats were divided into: Controls; PRE, which were fed a diet containing Synergy1; PRO, fed a diet containing LGG and Bb12; PREPRO, fed a diet containing Synergy1, LGG and BB12. Ten days after beginning the diets, rats were treated with AOM (15 mg/kg s.c. two times); dietary treatments were continued for the entire experiment. Thirty-one weeks after AOM, rats treated with Synergy1 (PRE and PREPRO groups) had a significantly lower (P < 0.001) number of tumours (adenomas and cancers) than rats without Synergy1 (colorectal tumours/rat were 1.9 +/- 1.7, 1.1 +/- 1.1, 2.2 +/- 1.4 and 0.9 +/- 1.2 in Controls, PRE, PRO and PREPRO groups, respectively, means +/- SD). A slight, not significant effect of probiotics in reducing malignant tumours was also observed (P = 0.079). Caecal short-chain fatty acids (SCFA) were higher (P < 0.001) in the groups treated with Synergy1. Apoptosis was increased in the normal mucosa of the PRO group, while no variation was observed in the tumours. Colonic proliferation was lower in the PRE group as compared with Controls. Glutathione S-transferase placental enzyme pi type expression, and to a lesser extent, inducible NO synthase were depressed in the tumours from rats in the PRE and PREPRO groups. Cycloxygenase-2 expression was increased in the tumours of control rats but not in those from PRE, PRO or PREPRO rats. In conclusion, prebiotic administration in the diet decreases AOM-induced carcinogenesis in rats.

Adenocarcinoma↗
PubMed2002

Hemizygous mice for the angiotensin II type 2 receptor gene have attenuated susceptibility to azoxymethane-induced colon tumorigenesis.

Evidence suggests that the use of angiotensin-converting enzyme inhibitors potentially reduces the risk of cancer, though the mechanism is unclear. To clarify a potential involvement of angiotensin II (Ang II) signaling in cancer risk, we have examined the effect of Ang II receptor deficiency on azoxymethane (AOM)-induced colon tumorigenesis. Male Ang II type 2 receptor gene-disrupted (AT(2)-null) mice with a 129/Ola and C57BL/6J genetic background, AT(2)-null mice with an SWR/J genetic background, and their corresponding control wild type mice were treated once a week with AOM (10 mg/kg, i.p., 4 consecutive weeks) or saline vehicle. All mice were killed 23-26 weeks after the initial injection of AOM, and tumor burdens were examined. AOM treatment caused the development of colon tumors in all wild type control mice regardless of genetic background (100% tumor prevalence), but only one tumor was present in AT(2)-null mice with a 129/Ola and C57BL/6J genetic background (11.1% tumor prevalence). Although the introduction of the AOMsusceptible SWR/J genetic background induced AOM susceptibility in AT(2) null mice, the tumor multiplicity (6.3) and tumor size (19.8 +/- 3.0 mm(3)) were significantly smaller than those in wild type mice (multiplicity, 12.0 and size, 36.8 +/- 3.2 mm(3)). AOM efficiently downregulated cytochrome P450 2E1 (CYP2E1) in the liver of wild type mice significantly more than in AT(2)-null mice. The levels of DNA methyl adducts formed in wild type mouse colon epithelium by AOM treatment were also significantly higher than in AT(2)-null mice. These results imply that the AT(2) receptor functions to augment AOM-induced downregulation of CYP2E1 expression in the liver, and thus increases AOM-induced tumorigenesis in the colon. The AT(2) receptor function in the liver may be a potential determinant of tumor susceptibility in chemical carcinogen-induced colon tumorigenesis.

Animals↗
PubMed2003

Azoxymethane-induced beta-catenin-accumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis.

It is now well established that bile acids act as colon tumor promoters. However, a previous study provided conflicting data showing that dietary exposure of cholic acid (CHA), a primary bile acid, inhibits the carcinogen-induced formation of aberrant crypt foci (ACF), possible preneoplastic lesions, in colonic mucosa of rodents. Recently we found beta-catenin-accumulated crypts (BCAC) in colonic mucosa of rats initiated with azoxymethane (AOM) and provided evidence that BCAC might be preneoplastic lesions independent from ACF. In the present study, we investigated the modifying effects of dietary CHA on the formation of BCAC as well as ACF in male F344 rats after exposure to AOM to determine if the differences in the effect of CHA on these lesions could account for this discrepancy. The results indicate that administration of CHA (0.5%) in the diet during the post-initiation phase significantly reduced the total number, multiplicity and size of ACF (P < 0.00001) in AOM-exposed colonic mucosa as reported previously. The number of ACF even with >4 aberrant crypts/focus was also decreased significantly (P < 0.0002), suggesting that the large ACF are little resistant to continuous feeding of 0.5% CHA diet. Interestingly, the dietary CHA significantly enhanced both the multiplicity (P < 0.002) and size (P < 0.00001), but not the incidence, of AOM-induced BCAC when compared with the control diet group. Importantly, the number of large BCAC with >6 crypts/lesion was increased significantly by the dietary CHA (P < 0.003). Our results support the concept that BCAC are precursors of colon tumors and indicate the usefulness of BCAC as intermediate biomarkers for colon carcinogenesis, although the methodology for their detection requires further improvement.

Animals↗
PubMed1983

Effect of dietary cholesterol on azoxymethane-induced colon carcinogenesis in rats.

The effect of dietary cholesterol on azoxymethane (AOM)-induced colon carcinogenesis was evaluated with two different sets of experiments. Starting at 6 weeks of age, male Donryu rats were divided into four groups, and fed either control chow or one supplemented with 1% cholesterol, and with or without AOM (11 weekly s.c. injections at a dosage of 7.4 mg/kg body weight). The rats were sacrificed at 20 weeks after (first experiment) and at 15 weeks after (second experiment) the last injection of AOM. The AOM-treated groups in both experiments developed tumors in the colon and small intestine, whereas no tumors were seen in the AOM-untreated groups. An interesting observation was that cholesterol feeding significantly increased the number of colon tumors/rat and the number of animals with distant metastases to several organs. Tumor growth and invasiveness were also enhanced, but not significantly. Both bile acids and neutral sterols in the feces were markedly increased in the rats fed the 1% cholesterol supplement (2-3 fold and 5-6 fold, respectively). According to these results, it might be postulated that dietary cholesterol revealed potent promoting effects on AOM-induced colon carcinogenesis through the mechanism of increasing excretion of bile acids and neutral sterols in the gut.

Animals↗
PubMed2004

Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice.

Epidemiological studies have shown that obesity and diabetes mellitus may be risk factors for colon cancer. However, the underlying mechanisms of how these chronic diseases promote colon carcinogenesis remain unknown. C57BL/KsJ-db/db mice have obese and diabetic phenotypes because of disruption of the leptin receptor. The present study was designed to investigate whether development of azoxymethane (AOM)-induced dysplastic and early neoplastic (premalignant) lesions of the colon is modulated in db/db mice. Homozygous db/db mice, heterozygous db/+ mice and littermate controls (+/+) were injected with AOM under food restriction ( approximately 10.8 kcal/mouse/day) and killed 5 weeks after the carcinogen treatment. Their colons were assessed for premalignant lesions induced by AOM. We found a significant increase in the multiplicity of the total premalignant lesions in db/db mice when compared with db/+ or +/+ mice. Phenotypically, serum leptin and insulin levels in db/db mice were significantly higher than those in db/+ or +/+ mice, whereas the body weights and glucose levels in blood of db/db, db/+ and +/+ mice were comparable. In addition, immunostaining of the leptin receptor and insulin-like growth factor-I receptor showed up-regulation of these protein levels specifically in the lesions. Our data indicate that development of AOM-induced premalignant lesions is enhanced in db/db mice with hyperleptinemia and hyperinsulinemia. The results have important implications for further exploration of the possible underlying events that affect the positive association between colon cancer and chronic diseases (obesity and diabetes).

Animals↗
PubMed2004

Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats.

Bovine lactoferrin, a multifunctional glycoprotein, has been shown to strongly inhibit development of azoxymethane (AOM)-induced rat colon tumors. Little, however, is known about the inhibitory mechanisms. We have demonstrated recently that lactoferrin enhances the expression of a member of the tumor necrosis factor receptor family, Fas, in the colon mucosa during both early and late stages of carcinogenesis. Thus, Fas could be involved in bovine lactoferrin-mediated inhibition of tumor development. To investigate this possibility, we studied the influence of bovine lactoferrin on Fas-mediated apoptosis with regard to expression of Fas, activation of caspase-8 and caspase-3, and DNA fragmentation in the colon mucosa of AOM-treated rats. Western blot analysis demonstrated a >2.5-fold increase in Fas protein expression, as well as elevation of the active forms of both caspase-8 and caspase-3. Immunohistochemical analysis revealed Fas-positive cells and apoptotic cells preferentially within the proximal colon region, clearly at the site of bovine lactoferrin-mediated tumor inhibition. These results suggest that apoptosis caused by elevated expression of Fas is involved in chemoprevention by lactoferrin of colon carcinogenesis.

Animals↗
PubMed2004

Azoxymethane-induced pre-adipocyte factor 1 (Pref-1) functions as a differentiation inhibitor in colonic epithelial cells.

Inbred mice differ dramatically in their sensitivity to the colon carcinogen, azoxymethane (AOM). Identifying genes associated with this differential susceptibility in mice may ultimately reveal molecular mechanisms responsible for colon carcinogenesis. A cDNA array approach was taken to study gene expression changes induced by AOM in the colons of sensitive (A/J) and resistant (AKR) mice. Among the genes represented on the array, pre-adipocyte factor 1 (Pref-1), associated previously with suppression of adipocyte differentiation, was induced specifically by AOM in the distal colons of sensitive A/J mice (5.4-fold). Reverse transcription-PCR followed by sequence analysis revealed the presence of four alternative splice variants of Pref-1 mRNA in the colon. The potential significance of Pref-1 in colon tumorigenesis was explored in colon cancer cells infected with a retroviral construct containing the major splice variant. Over-expression of Pref-1A in HT-29 cells led to a marked resistance to butyrate-induced differentiation and growth inhibition. Our data indicate that Pref-1, a protein that suppresses differentiation and promotes colonocyte growth, may account in part for the sensitivity of A/J mice to AOM-induced carcinogenesis. In addition, detection of Pref-1 in a human colon tumor cell line suggests that it may also participate in human colon tumorigenesis.

Alkaline Phosphatase↗
PubMed2005

Strain differences in the susceptibility to azoxymethane and dextran sodium sulfate-induced colon carcinogenesis in mice.

We have recently developed a mouse model for colitis-related colon carcinogenesis by a combined treatment with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male ICR mice. However, strain differences in the sensitivity to AOM/DSS-induced colon carcinogenesis in mice have yet to be elucidated. The aim of this study was to determine the presence of any genetically determined differences in sensitivity to our model of colon carcinogenesis in four inbred strains of mice. Male Balb/c, C3H/HeN, C57BL/6N and DBA/2N mice were given a single intraperitoneal injection of AOM (10 mg/kg body wt), followed by 1% DSS (w/v) in drinking water for 4 days, and thereafter they received no further treatment for up to 16 weeks. At the end of the study (Week 18), all mice were killed and a histopathological analysis of their colon was performed. The incidence of colonic adenocarcinoma was 100% with a multiplicity (no. of tumors/mouse) of 7.7+/-4.3 in the Balb/c mice and 50% with a multiplicity of 1.0+/-1.2 in the C57BL/6N mice. On the other hand, only a few colonic adenomas, but no adenocarcinomas, developed in the C3H/HeN mice (29% incidence with a multiplicity of 0.7+/-1.5) and the DBA/2N mice (20% incidence with a multiplicity of 0.2+/-0.4). The inflammation and immunohistochemical nitrotyrosine-positivity scores of the mice treated with AOM and DSS in the decreasing order were as follows: C3H/HeN>Balb/c>DBA/2N>C57BL/6N and Balb/c>C57BL/6N>C3H/HeN>DBA/2N, respectively. Our results thus indicated the presence of strain differences in the susceptibility to AOM/DSS-induced colonic tumorigenesis. These differences may have been directly influenced by the response to nitrosation stress due to the inflammation caused by DSS.

Adenocarcinoma↗
PubMed2006

Increased colon tumor susceptibility in azoxymethane treated CEABAC transgenic mice.

Human carcinoembryonic antigen (CEA), a widely used clinical tumor marker, and its close relative, CEACAM6, are often overexpressed in many cancers. This correlation suggests a possible instrumental role in tumorigenesis, which is supported by extensive results obtained with several in vitro systems. The implication that these results could also apply in vivo warrants investigation. Since mice do not possess homologs of the glycophosphatidyl inositol (GPI)-anchored CEACAM family genes CEA, CEACAM6 and CEACAM7, we have constructed transgenic mice harboring a 187 kb portion of the human CEACAM family gene locus contained in a bacterial artificial chromosome (CEABAC) that includes genes coding for CEA, CEACAM6 and CEACAM7. In this study, we treated the CEABAC mice and their wild-type littermates with azoxymethane (AOM) in order to induce colon tumor formation. At 20 weeks post-treatment, the CEABAC transgenics showed more than a 2-fold increase in mean tumor load relative to their wild-type littermates. Cell surface expression of CEA and CEACAM6 increased by 2- and 20-fold, respectively, in colonocytes from the tumors relative to colonocytes from non-AOM treated transgenics and a de-regulated spatial pattern of CEA/CEACAM6 expression was found in 'normal' crypts adjacent to the tumors, thus mimicking closely the situation in human colon tumorigenesis. A modestly increased incidence of beta-catenin mutations also observed in the AOM-induced CEABAC tumors. These results show that expression of the human GPI-anchored CEACAM family genes predisposes mice to acquire and/or retain essential mutations necessary for sporadic colon tumor development.

Animals↗
PubMed2003

Effect of age on susceptibility to azoxymethane-induced colonic aberrant crypt foci formation in C57BL/6JNIA mice.

To determine the effect of age on susceptibility to azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation and its underlying mechanism, young and old mice were injected with AOM weekly for 4 or 5 weeks and euthanized 5 or 6 weeks later. Given the same (12 or 15) mg/kg body weight dose of AOM, old mice had significantly more ACF than young mice. However, given the same total dose of AOM (to avoid confounding effect of higher dose to heavier old mice), at a low total dose (1.5 mg) there was no age difference, but at higher total doses (1.8 and 2.2 mg) young mice had significantly more ACF than old mice. These results indicate that the age-related susceptibility to AOM differs depending on whether administration of the carcinogen is based on weight or total dose. These age differences are not due to variations in cyclooxygenase-2 expression, cell proliferation, or AOM hydroxylase activity.

Age Factors↗
PubMed1994

Dietary carbohydrates modify azoxymethane-induced intestinal carcinogenesis in rats.

The effect of different dietary carbohydrates (sucrose, cornstarch and high amylose cornstarch) on intestinal carcinogenesis was studied in male Sprague-Dawley rats treated subcutaneously with azoxymethane (AOM) at a weekly dose of 8 mg/kg body wt for 8 wk. The diets, high in fat and low in calcium and fiber, were fed during and after AOM treatment. The number of colonic adenomas per rat in the groups fed either starch was lower (P < 0.05) than the number in the sucrose-fed rats [1.06 +/- 0.38, 0.30 +/- 0.10 and 0.41 +/- 0.22 (mean +/- SEM), in the sucrose-, cornstarch- and high amylose cornstarch-fed groups, respectively]. The incidence of total intestinal tumors (adenomas + adenocarcinomas) was not affected by dietary treatment. However, the incidence of tumors in the small intestine of the rats fed the two cornstarch diets tended to be slightly lower than for rats fed the sucrose diet (P = 0.075). Adenoma dysplasia and adenocarcinoma differentiation were similar among the rats fed the three diets. However, the adenocarcinomas in the rats fed the cornstarch diet were significantly smaller than those in the rats fed sucrose [0.99 +/- 0.14 cm2 (n = 13), 0.56 +/- 0.14 cm2 (n = 13) and 0.55 +/- 0.17 cm2 (n = 9) in rats fed the sucrose, cornstarch and high amylose starch diets, respectively]. Moreover, in the rats fed the cornstarch diet, the adenocarcinomas showed lower invasive potential than those in rats fed the sucrose diet. The results suggest an overall inhibition of AOM-induced carcinogenesis in rats fed the cornstarch diets.

Adenocarcinoma↗
PubMed1996

Dietary guar gum alters colonic microbial fermentation in azoxymethane-treated rats.

To assess the effects of guar gum on colonic microbial fermentation and cancer development, azoxymethane-treated rats were fed a partially hydrolyzed guar or control diet. Anaerobic fecal incubations were conducted at 8-wk intervals, either without added substrate or with cornstarch or hydrolyzed guar as substrates. Short-chain fatty acids in colonic contents and colonic carcinoma areas were measured at 27 wk. Fecal in vitro fermentation rates were higher for guar-fed rats than for control rats [three-way ANOVA (diet, time, in vitro substrates), P = 0.002]. Fecal in vitro butyrate production was greater for guar-fed rats than for control rats after 3-11 weeks of diet treatment (three-way ANOVA, P = 0.027). Butyrate concentrations of colonic contents at 27 wk were higher in guar-fed than in control rats and higher in the cecum than in the post-cecal colon (two-way ANOVA, P = 0.0001). A regression equation predicting colonic carcinoma area (r2 = 0.279) using propionate and butyrate concentrations of the contents of the post-cecal colon showed propionate as a positive predictor (P < 0.001) and butyrate as a negative predictor (P = 0.033). Our results show that patterns of short-chain fatty acid production may affect the results of fiber-carcinogenesis experiments. Dietary addition of hydrolyzed guar is associated with fecal fermentation low in propionate and high in butyrate; short-chain fatty acid concentrations are greater proximally than distally. These results suggest that butyrate protects against colonic neoplasia, whereas propionate enhances it, and demonstrate that colonic microbiota adapt to produce more butyrate if given time and the proper substrate.

Analysis of Variance↗
PubMed1997

Dry beans inhibit azoxymethane-induced colon carcinogenesis in F344 rats.

Epidemiological studies show a low incidence of colon cancer in many Latin American countries where the consumption of dry beans (e.g., pinto) is high. The purpose of this study was to use rats as an animal model to obtain experimental data on the inhibition of colon carcinogenesis by dry beans. Fifty-three 5-wk-old weanling male F344 rats were randomly assigned by weight to the following groups: control (11 rats), casein diet (21 rats), and bean diet (21 rats). Animals fed the casein and bean diets were treated with the carcinogen azoxymethane (AOM) once weekly for 2 wk. Rats in the control group also consumed the casein diet but were not exposed to AOM. All diets were isocaloric. The protein concentration of the diets was adjusted to 18 g/100 g with casein, and the fat concentration was adjusted to 5 g/100 g with corn oil. Rats fed the bean diet had significantly fewer colon adenocarcinomas (P < 0.05) than rats fed the casein diet (5 vs. 22 tumors), and significantly fewer rats fed the bean diet (P < 0.05) had colonic tumors than did casein-fed rats (24 vs. 50%). Tumor multiplicity was also significantly lower for the bean-fed rats, and significantly fewer (P < 0.05) tumors per tumor-bearing rat were observed in bean-fed rats than in casein-fed rats (1.0 +/- 0.0 vs. 2.5 +/- 0.6). This study demonstrates that dry beans contain anticarcinogenic compounds capable of inhibiting AOM-induced colon cancer in rats. However, the specific anticarcinogenic components within dry beans have not been identified, and it is unclear whether dietary fiber, phytochemicals or other components within dry beans are primarily responsible for the anticarcinogenic properties of beans.

Adenocarcinoma↗
PubMed1998

Fish oil blocks azoxymethane-induced rat colon tumorigenesis by increasing cell differentiation and apoptosis rather than decreasing cell proliferation.

The purpose of this study was to determine whether the protective effect of fish oil against colon carcinogenesis is due to decreased proliferation, increased differentiation and/or increased apoptosis. Male Sprague Dawley rats (n = 260) were fed one of two oils (corn or fish) and two fibers (pectin or cellulose), plus or minus the carcinogen azoxymethane (AOM). Rats were killed at wk 18 (n = 80) or 36 (n = 180) for cytokinetic measurements. In vivo cell proliferation was measured by incorporation of bromodeoxyuridine into DNA, differentiation by binding of Dolichos biflorus agglutinin and apoptosis by immunoperoxidase detection of digoxigenin labeled genomic DNA. Fish oil resulted in a lower adenocarcinoma incidence (56.1 vs. 70.3%) compared with corn oil. There was no effect of fat or fiber on number of proliferative cells/crypt column in either the proximal or distal colon. In contrast, fish oil resulted in a greater degree of differentiation compared with corn oil in both colonic sites. In addition, fish oil resulted in a higher number of apoptotic cells/crypt column in both the proximal and distal colon as compared with corn oil. AOM treatment increased the ratio of proliferative cells/crypt column to apoptotic cells/crypt column in both the proximal and distal colon compared with saline controls. Fish oil, however, resulted in a lower ratio in both sites in the colon as compared with corn oil. These results suggest that an increase in apoptosis and differentiation, rather than a decrease in proliferation, accounts for the protective effect of fish oil against experimentally induced colon tumorigenesis.

Adenocarcinoma↗
PubMed2001

Wheat aleurone flour increases cecal beta-glucuronidase activity and butyrate concentration and reduces colon adenoma burden in azoxymethane-treated rats.

Processed wheat aleurone flour (WAF) is a source of insoluble fermentable dietary fiber that comes from the outer layers of the wheat kernel. A study was designed to evaluate WAF, wheat bran (WB) and alpha-cellulose as the source of dietary fiber (5 g/100 g of diet) in a semipurified high fat (20 g/100 g of as 1:1 lard/sunflower seed oil) diet fed to male Sprague-Dawley rats in which intestinal tumors were induced using azoxymethane (AOM). WAF at 33 g/100 g of diet (WAF33) and WB at 16 g/100 g of diet (WB16) increased the weight of feces and produced significantly higher concentrations in the cecum of the short-chain fatty acid butyrate (P < 0.001) than did no fiber (NF) and WAF added at only 10 g/100 g (1.5 g of dietary fiber) (WAF10). Cecal and fecal pH were both significantly lower in the WAF33 and WB16 treatments relative to control and no fiber treatments (P < 0.001). The intestinal tumors in the rats were assessed at 6 mo after the study began, and the WAF33- or WB16-fed rats showed a trend (P = 0.06) with 43% fewer colon adenomas relative to control. There was a significant inverse relationship between ss-glucuronidase activity and colon adenomas in the rat colon (r2 = 0.37, P = 0.001). WAF fiber influenced some metabolic markers of fermentation in the colon in a manner similar to that of WB, which, independent of the bulking effect, was associated with a trend to reduced colon adenomas. Significantly increased cecal ss-glucuronidase activity and/or butyrate concentrations may have protective influences in this context by mechanisms not yet fully elucidated.

Adenoma↗
PubMed2002

A diet containing alpha-cellulose and fish oil reduces aberrant crypt foci formation and modulates other possible markers for colon cancer risk in azoxymethane-treated rats.

There is a need for better understanding of the roles of dietary fats and fibers in colon cancer risk. We examined the effect of different dietary fiber and fat sources on an azoxymethane (AOM)-induced colon cancer in rats. In a 2 x 3 factorial design, rats were fed a semipurified diet containing soy-derived fiber (Fibrim), alpha-cellulose (Solkafloc) or resistant starch (RS; Hi-maize) at 10 g dietary fiber/100 g diet, combined with fish oil (FO) or sunflower seed oil (SSO) at 10 g/100 g diet, and lard added to all diets at 10 g/100 g, to provide a total of 20 g mixed fat/100 g diet. Sprague-Dawley rats (28 d of age) consumed diets for 4 wk and then two doses of AOM (15 mg/kg body) were administered 1 wk apart by subcutaneous injection. Rats were killed after 13 wk of consuming experimental diets. Colons were fixed in formalin and aberrant crypt foci (ACF) were quantified after staining. ACF counts were higher (+66%, P < 0.01) in rats fed SSO and RS, than in those fed alpha-cellulose and FO. Rats fed FO had 19% fewer ACF than those fed SSO (P < 0.05). alpha-Cellulose was associated with the highest cecal butyrate concentration (P < 0.001), the highest beta-glucuronidase specific activity (P < 0.001) and the lowest cecal water cytotoxicity (P < 0.001) relative to soy fiber- and RS-fed rats. There were inverse correlations between the number of ACF and cecal butyrate concentration (r = -0.33, P < 0.05) and between cecal water cytotoxicity and beta-glucuronidase activity (r = -0.70, P < 0.001). The greatest protection was associated with alpha-cellulose as the fiber source and FO as the fat source as measured by colon ACF numbers in rats.

Animal Feed↗
PubMed2002

Dietary inulin suppresses azoxymethane-induced preneoplastic aberrant crypt foci in mature Fisher 344 rats.

Preneoplastic aberrant crypt foci (ACF) are generally accepted as reliable markers for colon carcinogenesis in animal models. Rat model ACF studies, however, use younger rats, and there are no published reports on the suitability of adult rats for ACF studies. In this study, inulin, a known suppressor of azoxymethane (AOM)-induced ACF, was tested for its ability to suppress ACF formation in mature rats. After a 2-wk acclimation period, 12-mo-old Fisher 344 retired male breeders received two subcutaneous injections of AOM dissolved in saline at weekly intervals. In experiment 1, six groups received 0, 4, 8, 10, 12 and 16 mg AOM/kg body at each injection and were fed AIN-93M diet. In experiment 2, four groups of rats were fed 10 mg AOM/kg body at each injection based on the results of experiment 1, and were fed 0, 2.5, 5 and 10 g long-chain inulin diets/100 g. All the rats were killed after 11-wk feeding periods. In experiment 1, there was a significant (P < 0.05) AOM dose response on ACF formation. Rats fed >10 mg of AOM had greater (P < 0.05) mortality. In experiment 2, there was a significant increase in cecal weight and a decrease in cecal pH from 7.17 in the control group to 6.87, 6.61 and 5.76 in the groups fed inulin at 2.5, 5.0 and 10 g/100 g, respectively. Long-chain inulin dose-dependently reduced ACF incidence in the colon (P < 0.01). Compared with rats fed the control diet, the percentage reductions of ACF in rats fed 2.5, 5.0 and 10 g inulin diets/100 g were 25, 51, and 65, respectively. The results of this study indicate that mature rats can be used as models in ACF studies, and dietary long-chain inulin dose-dependently suppresses AOM-induced ACF formation in Fisher 344 mature male rats.

Age Factors↗