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PubMed1997

Wheat bran diet reduces tumor incidence in a rat model of colon cancer independent of effects on distal luminal butyrate concentrations.

To investigate the effects of dietary fibers in colonic luminal physiology and their role in the prevention of colon cancer, a study was conducted using two diet groups and two treatment groups in a 2 x 2 factorial design. The two diets differed only in the type of dietary fiber, wheat bran and oat bran, and the two treatments were injection with the colon-specific carcinogen azoxymethane, or saline, as a control. There were 34 rats in the carcinogen-injected groups and 11 saline-injected rats per diet group. The goal of the study was to determine if a moderate consumption (6 g/100 g diet) of wheat bran or oat bran would alter the development of colonic tumors in this rat model of colon cancer, and if the differences in tumor incidence were correlated to luminal butyrate concentrations, luminal pH or fecal bulk. Short-chain fatty acid concentrations (SCFA) were measured in feces during the first half of the study (the promotion phase of tumor development) and again at the end of the study. Rats consuming oat bran had greater body weights (P < 0. 002), produced much larger concentrations of all SCFA, including butyrate, in both the proximal and distal colon (P < 0.0001), had more acidic luminal pH values (P < 0.0001), but also had significantly more development of colon tumors (P < 0.03). Alternatively, rats consuming wheat bran produced more typical molar ratios of the SCFA (65:10:20), had a relatively greater concentration of butyrate than propionate, and produced a larger volume (P < 0.05) and more bulky stool than the rats fed oat bran. The results of this study support other evidence that an acidic luminal pH is not protective in and of itself, and that diets containing wheat bran are protective against colon cancer development. In addition, these data show that large luminal butyrate concentrations in the distal colon alone, as were present in the rats consuming oat bran diets, are not protective of tumor development.

Animals↗
PubMed1997

Diet and carcinogen alter the fecal microbial populations of rats.

An analysis of viable bacterial populations enumerated on carbohydrate selective media was used to simulate the colonic environment in vitro and determine if differential media could detect significant microbial shifts due to dietary fiber source, dietary fat source, and carcinogen. Male Sprague-Dawley rats were provided with either pectin or cellulose as a fiber source, either corn or fish oil as a source of fatty acids, and injected with either azoxymethane (AOM), a gastrointestinal carcinogen, or saline in a 2 x 2 x 2 factorial design. At 6 and 10 mo of age, fresh feces were collected, homogenized in anaerobic buffer and anaerobically plated onto differential media. Diets containing pectin supported more anaerobes at 6 mo of age (P < 0.01) than diets containing cellulose. Rats injected with AOM and consuming either pectin or corn oil supported more anaerobes at 10 mo of age (P < 0.05) than rats injected with saline and consuming the same diets. Rats consuming cellulose and receiving AOM but not expressing tumors possessed larger anaerobic populations at 10 mo of age (P < 0.05) than rats consuming cellulose, injected with AOM and expressing tumors. These effects show that gastrointestinal bacterial populations, as measured by carbohydrate specific media, respond to dietary changes such as dietary fiber source, and thus may play a key role in the etiology of colon cancer.

Aging↗
PubMed1998

Iron supplementation does not affect cell proliferation or aberrant crypt foci development in the colon of sprague-dawley rats.

It has been suggested that high iron stores enhance colon carcinogenesis. The effect of high dietary iron (Fe) on indices of iron, copper (Cu) and manganese (Mn) status, lipid peroxidation using the thiobarbituric acid reactive substances assay, superoxide dismutase, glutathione peroxidase, glutathione transferase and ceruloplasmin activities, cell proliferation and development of preneoplastic lesions known as aberrant crypt foci (ACF) in rat colon was examined using a 3 x 2 factorial design. Male weanling Sprague-Dawley rats were fed adequate (AFe; 45 mg Fe/kg diet), moderately high (MHFe; 225 mg Fe/kg diet) and high (HFe; 450 mg Fe/kg diet) dietary Fe for 2.5 wk, then treated with azoxymethane (AOM; 2 injections, 1 wk apart; total dose 30 mg/kg body weight) or saline (n = 14-15 per group). Dietary treatment continued for another 6 wk after the second AOM dose. At the time of AOM injection, colon Fe concentrations were one- and threefold higher for MHFe and HFe rats, respectively, than for AFe rats. It was proposed that high dietary Fe would adversely affect Cu and Mn status, resulting in impaired antioxidant enzyme activity. However, neither indices of Cu and Mn status nor colonic mucosal antioxidant enzyme activities were affected by dietary Fe except for plasma ceruloplasmin activity, which was slightly lower in rats fed high iron diets than in rats fed adequate iron diets (P < 0.01). Dietary Fe had no significant effect on colonic mucosal lipid peroxidation, cell proliferation or ACF development. In conclusion, our findings suggest that dietary Fe concentrations that are approximately 5 and 10 times adequate do not enhance oxidative stress, cell proliferation and ACF development in the colon of rats.

Animals↗
PubMed1998

Energy metabolism of rat colonocytes changes during the tumorigenic process and is dependent on diet and carcinogen.

Alterations in ATP production, intracellular energy levels and mitochondrial function have been shown to trigger cytokinetic events in vitro, including inhibition of cell division, abnormal or blocked differentiation and inhibition of apoptosis. Changes in colonic cytokinetics are directly related to colon tumorigenesis but alterations in energy metabolism during the tumorigenic process have never been reported. We conducted a 2 x 2 x 3 factorial design study in 120 male Sprague-Dawley rats with two diets (pectin or cellulose-supplemented), two injected subgroups (with or without the carcinogen azoxymethane, AOM) and three termination time points (6, 16 and 36 wk post-second injection). Colonocytes were isolated and incubated with their primary energy substrates (radiolabeled butyrate, glucose, glutamine and beta-hydroxybutyrate) for 60 min. Production of lactate, ketone bodies and CO2 were determined. At 6 wk, there were no significant differences in metabolism among treatments. In contrast, at 16 wk, AOM-injected rats had dramatically lower rates of CO2 production (P < 0.001) from both glucose and butyrate and lower rates of lactate and ketone body production than their saline counterparts. At 36 wk, when tumors developed, the depressed production of lactate and ketone bodies seen in AOM-injected rats at 16 wk returned to control values. However, in AOM-injected rats, CO2 production from glucose and butyrate remained depressed. Cellulose feeding resulted in decreased oxidation of glucose, butyrate and glutamine and an increased production of ketone bodies from butyrate by colonocytes compared with pectin feeding at 36 wk. We conclude that colonocyte energy metabolism differs in AOM-injected rats vs. saline controls and changes during tumorigenesis, and suggest a relationship between intracellular energy status and changes in cell kinetics. This is the first report that such a relationship may exist in vivo.

3-Hydroxybutyric Acid↗
PubMed2004

Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type mice from carcinogen-induced colon cancer.

Consumption of soy foods has been weakly associated with reduced colon cancer risk. Colon cancer risk is influenced by estrogen exposure, although the mechanism through which this occurs is not defined. Conversion of estradiol (E2) to estrone (E1) may be protective in the colon. We hypothesized that dietary phytoestrogens, or E1, would reduce colon tumorigenesis via an estrogen receptor (ER)-dependent mechanism. Ovariectomized ERalphaKO or wild-type (WT) female mice were fed diets containing casein (Casein), soy protein without isoflavones (Soy-IF), soy protein + genistein (Soy+Gen), soy protein + NovaSoy (Soy+NSoy) or soy protein + estrone (Soy+E1) from weaning. Colon tumors were induced with azoxymethane. Tumor incidence was affected by diet but not genotype. Colon tumor incidence was lower in ERalphaKO and WT mice fed the Soy+E1 diet compared with those fed the casein or Soy-IF diets. Mice fed Soy+NSoy had a lower tumor incidence than mice fed casein, but not Soy-IF. Genistein did not affect tumor incidence. Soy protein, independently of phytoestrogens or E1, significantly reduced relative colon weight, tumor burden and multiplicity. Relative colon weight was lower (P=0.008) in mice fed Soy+E1 than in the other soy-fed groups. Tumor incidence in this group was lower than in the casein and soy-IF-fed groups and tended to be lower than in the others (P=0.020). Hence, soy protein and NSoy protect mice from colon cancer, and E1 further reduces colon tumorigenesis in mice, independently of ERalpha.

Animals↗
PubMed2004

Dietary sodium gluconate protects rats from large bowel cancer by stimulating butyrate production.

Butyrate has an antitumorigenic effect on colorectal cancer cell lines. Dietary sodium gluconate (GNA) promotes butyrate production in the large intestine. Accordingly, we examined the effect of dietary GNA on tumorigenesis in the large intestine in rats. Male Fisher-344 rats (n = 32) were divided into 4 groups: 2 diets (with or without 50 g GNA/kg basal diet) x 2 treatments (with or without carcinogen administration). Colonic tumors were induced by 3 intraperitoneal injections of azoxymethane (15 mg/kg body wt, 1 time/wk) and dietary deoxycholic acid (2 g/kg basal diet). The experiment was conducted for 33 wk except for a few rats. Ingestion of GNA increased cecal butyrate concentration at the end of experiment (P < 0.01). No tumor development occurred in the untreated groups. Ingestion of GNA decreased the incidence of tumors in rats administered the carcinogen (37.5 vs. 100%, P < 0.05). Ingestion of GNA also decreased the mean number of tumors per rat (0.5 +/- 0.8 vs. 2.8 +/- 1.5, P < 0.01). beta-Catenin accumulation and TdT-mediated dUTP nick end labeling (TUNEL) positive cells in tumors were histochemically examined. The results of this study suggested that the antitumorigenic effect of GNA may involve the stimulation of apoptosis through enhanced butyrate production in the large intestine.

Adenocarcinoma↗
PubMed1986

Effect of different levels of dietary corn oil and lard during the initiation phase of colon carcinogenesis in F344 rats.

The effect of various levels of polyunsaturated fat (corn oil) and saturated fat (lard) fed during the initiation stage of colon carcinogenesis was studied in male F344 rats. The animals were fed the diets containing 5, 13.6, and 23.5% corn oil or lard 2 weeks before, during, and until 1 week after sc injection of 15 mg azoxymethane [(AOM) CAS: 25843-45-2]/kg body weight, once weekly for 2 weeks (designated as initiation). One week after AOM treatment, groups of animals were transferred to their respective 5% corn oil or lard diets. Additional groups consuming 5% corn oil or lard were transferred to 23.5% corn oil or lard, respectively (post-initiation stage). All animals were fed these diets until the termination of the experiment. Fecal bile acids and colonic mucosal ornithine decarboxylase activity were measured in vehicle-treated animals fed the experimental diets for 14 weeks. Body weights and intakes of total calories, protein, nonnutritive fiber, and micronutrients were comparable among the various dietary groups. The animals fed the 23.5% corn oil diet during the postinitiation stage had a higher incidence of colon tumors than did those fed the 5% corn oil diet, whereas feeding of 23.5 and 13.6% corn oil diets during the initiation stage had no effect. In contrast, animals fed the 23.5 and 13.6% lard diet during the initiation stage and 23.5% lard diet during the postinitiation stage developed more colon adenocarcinomas than did those fed the 5% lard diet. The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid and the activity of colonic mucosal ornithine decarboxylase activity were higher in animals fed the 23.5% corn oil or lard diet during the postinitiation compared to the levels in animals fed the 5% corn oil or lard diet.

1,2-Dimethylhydrazine↗
PubMed1989

Effects of timing of administration and dose of difluoromethylornithine on rat colonic carcinogenesis.

During azoxymethane (AOM)-induced colonic carcinogenesis in rats, biphasic induction of ornithine decarboxylase (ODC) activity occurs in the colonic mucosa. The relative contributions of these two phases of ODC induction to the carcinogenesis process were examined by studying the effects of the specific ODC inhibitor, difluoromethylornithine (DFMO), administered during either the initial phase of ODC increase or during both phases continuously. The effects of 1% and 0.25% DFMO administered continuously were also compared. Continuous oral administration of DFMO at 1% (approximately 8 mg/g body wt/wk) and 0.25% (approximately 2 mg/g body wt/wk) produced 93% inhibition of ODC induction by AOM in the right and left colons throughout the study. Despite suppression of ODC activity to near-normal levels, colon tumor incidence at 26 weeks in the right colon was not affected by either initial-phase or continuous administration of DFMO. In contrast, tumor incidence in the left colon was reduced from 35% to 5% by DFMO given continuously at doses of both 1% and 0.25% over the entire 26 weeks (P less than .05). No significant reduction in left colon tumor incidence resulted from the short initial 11-week course of DFMO although the tumor incidence was reduced (15% vs. 35%). Results suggest that the second ("post-initiation") phase of ODC induction may be of particular importance in carcinogenesis.

Animals↗
PubMed2005

Sphingosine kinase 1 is up-regulated in colon carcinogenesis.

Sphingosine kinase 1 (SK1) phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has the ability to promote cell proliferation and survival and stimulate angiogenesis. The SK1/S1P pathway also plays a critical role in regulation of cyclooxygenase-2 (COX-2), a well-established pathogenic factor in colon carcinogenesis. Therefore, we examined the expression of SK1 and COX-2 in rat colon tumors induced by azoxymethane (AOM) and the relationship of these two proteins in normal and malignant intestinal epithelial cells. Strongly positive SK1 staining was found in 21/28 (75%) of rat colon adenocarcinomas induced by AOM, whereas no positive SK1 staining was observed in normal mucosa. The increase in SK1 and COX-2 expression in AOM-induced rat colon adenocarcinoma was confirmed at the level of mRNA by real-time RT-PCR. In addition, it was found that 1) down-regulation of SK1 in HT-29 human colon cancer cells by small interfering RNA (siRNA) decreases COX-2 expression and PGE2 production; 2) overexpression of SK1 in RIE-1 rat intestinal epithelial cells induces COX-2 expression; and 3) S1P stimulates COX-2 expression and PGE2 production in HT-29 cells. These results suggest that the SK1/S1P pathway may play an important role in colon carcinogenesis, in part, by regulating COX-2 expression and PGE2 production.

Animals↗
PubMed1997

The ability of two cooked food mutagens to induce aberrant crypt foci in mice.

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.

Analysis of Variance↗
PubMed2006

Chemopreventive potential of diallylsulfide, lycopene and theaflavin during chemically induced colon carcinogenesis in rat colon through modulation of cyclooxygenase-2 and inducible nitric oxide synthase pathways.

Chemoprevention of colorectal cancer has become essential in the modern industrialized world as cancer of the large bowel has become one of the major causes of cancer mortality, second only to lung cancer. Colon cancer integrates lifestyle factors and multistep genetic alterations, and without preventive intervention, a substantial part of the population is likely to develop colorectal cancer at some point during their lives. Diet and nutrition clearly play a role in the etiology of colon cancer. Inhibitory activity of aqueous suspensions of garlic, tomato and black tea was tested on azoxymethane-induced colon carcinogenesis in Sprague-Dawley rats during earlier studies. In the present study, the protective activity of diallylsulfide and lycopene and theaflavin, important antioxidative ingredients of garlic, tomato and black tea, respectively, was assessed during colon carcinogenesis. The effect was observed on aberrant crypt foci, the preneoplastic lesion. As inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activities is correlated with the prevention of colon cancer, the study continues with the determination of the change in the expression of these proteins. Following treatment, significant reduction in the incidences of aberrant crypt foci (by 43.65% in diallylsulfide, 57.39% in lycopene and 66.08% in theaflavin group) was observed, which was in accordance with the reduced expression of cyclooxygenase-2 and inducible nitric oxide synthase. The effect of the intact source was found to be more pronounced than their components used separately.

Allyl Compounds↗
PubMed1990

Identification of a protein increasing in serum of Nagase analbuminemic rats bearing intestinal tumors as an isotype of T-kininogen.

Increase in an unidentified protein was observed in serum of Nagase analbuminemic rats (NAR) bearing intestinal tumors induced by azoxymethane. This protein seemed to be a polymer of a protein of 73 kDa as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and so was tentatively named 73K-protein. The serum concentration of 73K-protein in NAR bearing intestinal tumors was 11.9 +/- 2.2 mg/ml (mean +/- SD, n = 5), whereas that in control NAR was 2.0 +/- 0.2 mg/ml. Increase of the serum 73K-protein level was also observed in Sprague-Dawley rats bearing intestinal tumors, skin tumors, subcutaneous sarcomas, or mammary tumors and in ACI rats bearing urinary bladder tumors. On double immunodiffusion analysis, the 73K-protein was not detected in mouse, guinea pig, pig, horse, or human serum. A cDNA clone bearing the sequence encoding 73K-protein was isolated from a cDNA library constructed from rat liver mRNA. The nucleotide sequence of the 73K-protein showed 98.8% and 96.9% homologies with the sequences of the 3'-proximal domains of the cDNAs for TI- and TII-kininogen, respectively. Therefore, the 73K-protein was concluded to be an isotype of T-kininogen.

Amino Acid Sequence↗
PubMed1998

Prevention of N-methylnitrosourea-induced colon tumorigenesis by ursodeoxycholic acid in F344 rats.

Bile acids are known to promote colon carcinogenesis. However, there is one study showing that ursodeoxycholic acid (UDCA) supplemented in the diet at the concentration of 0.4% prevented azoxymethane-induced rat colon tumorigenesis. The aim of our study was to explore the inhibitory effect of a much smaller dose of UDCA on colon carcinogenesis in rats. One hundred 7-week-old F344 rats were given 2 mg of N-methylnitrosourea 3 times a week for 3 weeks by intrarectal instillation, and were fed a 0% (control), 0.4% or 0.08% UDCA-supplemented diet for the next 27 weeks. All the rats were killed and examined for tumor development at week 30. The tumor incidence and number were significantly lower and smaller, respectively, in the UDCA-fed rats than in the control rats: 40% and 36% vs. 68%; 0.5 +/- 0.1 (mean +/- SEM) and 0.4 +/- 0.1 vs. 1.0 +/- 0.2. All the tumors were located in the distal half of the colon and were plaque-shaped or polypoid, being well-differentiated adenocarcinomas restricted to the mucosa or submucosa. Bile acids in the feces and the blood obtained at weeks 20 and 30, respectively, were analyzed by HPLC. A significant increase of UDCA was confirmed in both the feces and the blood of the UDCA-fed rats compared with the control rats. The results suggest that the continuous feeding of a small dose of UDCA may prevent colon carcinogenesis.

Animals↗
PubMed2001

Troglitazone, a ligand for peroxisome proliferator-activated receptor gamma, inhibits chemically-induced aberrant crypt foci in rats.

The biological roles of peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, have been highlighted recently. Although PPARgamma ligand is suspected to play an important role in carcinogenesis, its effects on colon tumorigenesis remain undetermined. The present time-course study was conducted to investigate possible modifying effects of a PPARgamma ligand, troglitazone, on the development and growth of aberrant crypt foci (ACF), putative precursor lesions for colon carcinoma, induced by azoxymethane (AOM) or dextran sodium sulfate (DSS) in male F344 rats. Oral troglitazone (10 or 30 mg / kg body weight (b.w.)) significantly reduced AOM (two weekly subcutaneous injections, 20 mg / kg b.w.)-induced ACF. Treatment with troglitazone increased apoptosis and decreased polyamine content and ornithine decarboxylase (ODC) activity in the colonic mucosa of rats treated with AOM. Gastric gavage of troglitazone also inhibited colitis and ACF induced by DSS (1% in drinking water), in conjunction with increased apoptosis and reduced colonic mucosal polyamine level and ODC activity. Our results suggest that troglitazone, a synthetic PPARgamma ligand, can inhibit the early stage of colon tumorigenesis with or without colitis.

Animals↗
PubMed2001

Suppression of occurrence and advancement of beta-catenin-accumulated crypts, possible premalignant lesions of colon cancer, by selective cyclooxygenase-2 inhibitor, celecoxib.

Suppression of occurrence and advancement of premalignant lesions is important for cancer prevention. Our previous studies clarified that beta-catenin-accumulated crypts, independent of aberrant crypt foci (ACF), are probably direct precursors of colon cancers in rats. Here we investigated the effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on the development of beta-catenin-accumulated crypts in comparison with those on ACF. Male F344 rats were divided into 4 groups. Groups 1 - 3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg / kg body weight, once weekly for 3 weeks to induce beta-catenin-accumulated crypts. Groups 2 and 3 also received experimental diet containing celecoxib (500 and 1500 ppm, respectively) for 8 weeks, starting a week before the first dosing of AOM. At termination, the frequency and crypt multiplicity (number of crypts / lesion) of beta-catenin-accumulated crypts of groups 2 and 3 were significantly less than that of group 1. Furthermore, numbers of silver-stained nucleolar organizer regions (AgNORs) / nucleus in beta-catenin-accumulated crypts were also decreased by exposure to celecoxib. In this study, celecoxib had greater effects on the frequency and growth of beta-catenin-accumulated crypts than on those of ACF. These findings represent additional evidence that beta-catenin-accumulated crypts are premalignant lesions of colon cancer. The results also suggest that beta-catenin-accumulated crypts could be a novel target for evaluation of possible chemopreventive agents against colon carcino-genesis, and indicate that possible chemopreventive effects of celecoxib on the initial stage of colon carcinogenesis may be related to modulation of cell proliferation activity in such early lesions.

Animals↗
PubMed2005

Beta-Catenin mutations in a mouse model of inflammation-related colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sodium sulfate.

In a previous study, we developed a novel mouse model for colitis-related carcinogenesis, utilizing a single dose of azoxymethane (AOM) followed by dextran sodium sulfate (DSS) in drinking water. In the present study, we investigated whether colonic neoplasms can be developed in mice initiated with a single injection of another genotoxic colonic carcinogen 1,2-dimethylhydrazine (DMH), instead of AOM and followed by exposure of DSS in drinking water. Male crj: CD-1 (ICR) mice were given a single intraperitoneal administration (10, 20 or 40 mg/kg body weight) of DMH and 1-week oral exposure (2% in drinking water) of a non-genotoxic carcinogen, DSS. All animals were killed at week 20, histological alterations and immunohistochemical expression of beta-catenin, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) were examined in induced colonic epithelial lesions (colonic dysplasias and neoplasms). Also, the beta-catenin gene mutations in paraffin-embedded colonic adenocarcinomas were analyzed by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. The incidences of colonic neoplasms with dysplastic lesions developed were 100% with 2.29+/-0.95 multiplicity, and 100% with 10.38+/-4.00 multiplicity in mice given DMH at doses of 10 mg/kg or 20 mg/kg and 2%DSS, respectively. Although approximately half of the mice given DMH at a dose of 40 mg/kg bodyweight were dead after 2-3 days after the injection, mice who received DMH 40 mg/kg and 2%DSS had 100% incidence of colonic neoplasms with 9.75+/-6.29 multiplicity. Immunohistochemical investigation revealed that adnocarcinomas, induced by DMH at all doses and 2%DSS, showed positive reactivities against beta-catenin, COX-2 and iNOS. In DMH/DSS-induced adenocarcinomas, 10 of 11 (90.9%) adenocacrcinomas had beta-catenin gene mutations. Half of the mutations were detected at codon 37 or 41, encoding serine and threonine that are direct targets for phosphorylation by glycogen synthase kinase-3beta. The present results suggests that, as in the previously reported model (AOM/DSS) our experimental protocol, DMH initiation followed by DSS, may provide a novel and useful mouse model for investigating inflammation-related colon carcinogenesis and for identifying xenobiotics with modifying effects.

1,2-Dimethylhydrazine↗
PubMed2006

Inhibition of intestinal carcinogenesis by a new flavone derivative, chafuroside, in oolong tea.

A new flavone derivative, chafuroside, has been isolated as a strong anti-inflammatory compound from oolong tea leaves, and its structure determined to be (2R,3S,4S,4aS,11bS)-3,4,11-trihydroxy-2-(hydroxymethyl)-8-(4-hydroxyphenyl)-3,4,4a,11b-tetrahydro-2H,10H-pyrano[2',3':4,5]furo[3,2-g]chromen-10-one. To assess its potential to inhibit intestinal carcinogenesis, 2.5, 5 and 10 p.p.m. chafuroside was given in the diet to Apc-deficient Min mice for 14 weeks from 6 weeks of age. Total numbers of polyps were reduced to 83, 73 and 56% of the control value, respectively. Moreover, dietary administration at 10 and 20 p.p.m. reduced azoxymethane (AOM)-induced colon aberrant crypt foci (ACF) development in rats to 69% of the AOM-treated control value with the higher dose. Chafuroside-associated toxicity was not observed at 2.5-10 p.p.m. in Min mice and 10-20 p.p.m. in AOM-treated rats. These results suggest that chafuroside might be a good chemopreventive agent for colon cancer.

Animals↗
PubMed2005

Increased microvascular blood content is an early event in colon carcinogenesis.

BACKGROUND: Increased premalignant epithelial microvascular blood content is a common theme in neoplastic transformation; however, demonstration of this phenomenon in colon carcinogenesis has been stymied by methodological limitations. Our group has recently developed a novel optics technology, four dimensional elastic light scattering fingerprinting (4D-ELF), which allows examination of the colonic mucosal architecture with unprecedented accuracy. In this study, we utilised 4D-ELF to probe the preneoplastic colonic microvasculature. METHODS: Colonic mucosal blood content was assessed by 4D-ELF at serial preneoplastic time points from azoxymethane (AOM) treated Fisher 344 rats and age matched control animals. We also examined the pretumorigenic intestinal mucosa of the MIN mouse, and compared with wild-type mice. Finally, in a pilot study, we examined superficial blood content from the endoscopically normal mid transverse colon in 37 patients undergoing screening colonoscopy. RESULTS: In the AOM treated rat model, augmentation of superficial mucosal and total mucosal/superficial submucosal blood supply preceded the appearance of aberrant crypt foci (ACF) and temporally and spatially correlated with future ACF occurrence. These findings were replicated in MIN mice. The 4D-ELF based results were corroborated with immunoblot analysis for haemoglobin on mucosal scrapings from AOM treated rats. Moreover, 4D-ELF analysis of normal human colonic mucosa indicated that there was a threefold increase in superficial blood in patients who harboured advanced adenomas. CONCLUSION: We report, for the first time, that blood content is increased in the colonic microvasculature at the earliest stages of colon carcinogenesis. These findings may provide novel insights into early biological events in colorectal carcinogenesis and have potential applicability for screening.

Adenoma↗