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PubMed1993

Reduction of aberrant crypt foci induced in rat colon with azoxymethane or methylnitrosourea by feeding cholic acid.

Recent studies in our laboratory have demonstrated that feeding cholic acid (CHA) to rats treated with a single dose of azoxymethane (AOM) reduces the growth of putative preneoplastic lesions, aberrant crypt foci (ACF), in a dose-dependent manner. This finding was unexpected since CHA has been reported to promote colon cancer in rats receiving multiple treatments of the colon carcinogen, methylnitrosourea (MNU). The main objective of the present investigation was to evaluate the effect of the type of carcinogen and treatment protocol on the induction and growth of ACF in conjunction with CHA treatment. Male Sprague-Dawley rats received 0, 1 or 2 treatments with AOM or MNU and were fed either the AIN-76A or AIN-76A plus 0.2% CHA diet for 4 weeks. The total number and average size of ACF were significantly reduced in CHA-fed animals regardless of the type or number of treatments of carcinogen. The greatest reduction of ACF due to CHA-feeding was seen in the distal colon. The average crypt multiplicity (number of crypts in each ACF) was not altered by diet or carcinogen treatment. Colonic cell proliferation (crypt height and number of mitotic figures) was significantly increased in CHA-fed animals compared to control diet animals. Therefore, feeding CHA for 4 weeks reduced the number and size of ACF in rats induced by 1 or 2 injections of AOM or MNU, despite stimulation of colonic cell proliferation. These findings suggest further investigation is needed to understand the mechanism of promotion by cholic acid and the value of number and growth characteristics of ACF as a biological endpoint in the pathogenesis of colon cancer.

Analysis of Variance↗
PubMed1993

Effect of restricted caloric intake on the development of the azoxymethane-induced glutathione S-transferase placental form positive hepatocellular foci in male F344 rats.

The modifying effect of 30% caloric restriction on the occurrence of azoxymethane (AOM)-induced glutathione S-transferase placental form (GST-P) positive hepatocellular foci was investigated in male F344 rats. Starting at 5 weeks of age, groups of animals were fed ad libitum a high-fat (23.5%) semipurified diet. At 7 weeks of age, all animals except the vehicle-treated groups were s.c. injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). Four days after the second injection, groups of animals were continued on high-fat diet and fed ad libitum (ad libitum group) whereas other groups were restricted to 70% of total calories (calorie-restricted group) consumed by the ad libitum group, but received the same amounts of fiber, vitamins and minerals. Thirty-two weeks after AOM injections, all animals were necropsied and livers were sectioned and stained for GST-P by a immunohistochemical technique for quantitative analysis of enzyme altered foci of the liver. Comparing AOM treated groups. The density and the unit area of enzyme altered foci were significantly lower in the calorie-restricted group (3.84 +/- 1.55/cm2, 7.96 +/- 5.43%) than in the ad libitum group (10.14 +/- 3.62/cm2, 28.11 +/- 12.33%). The size of foci was also reduced in the calorie-restricted group (17.15 x 10(-3) mm2 vs. 32.36 x 10(-3) mm2). The incidence and density of hepatocellular foci in rats fed calorie restricted diet were significantly lower than those in rats fed ad libitum, comparing vehicle-treated groups. These results indicate that calorie restriction inhibited the occurrence of both of spontaneous and AOM induced GST-P positive foci in rats.

Animals↗
PubMed1994

Chemopreventive effect of costunolide, a constituent of oriental medicine, on azoxymethane-induced intestinal carcinogenesis in rats.

Modifying effects of costunolide, a constituent of oriental medicines, on intestinal carcinogenesis were examined in a rat model using azoxymethane (AOM). A total of 115 male F344 rats, 6 weeks old, were divided into four groups. Group 1 (30 rats) was fed a diet containing costunolide at a concentration of 0.02% for 4 weeks during which time three s.c. injections of AOM (15 mg/kg) were applied, and then kept on a basal diet until the end of the experiment (33 weeks). Group 2 (30 rats) was given AOM as in group 1 and fed the basal diet throughout, without costunolide. Group 3 (25 rats) was administered costunolide at the start of the experiment, but not given the carcinogen. Group 4 (30 rats) received the basal diet alone throughout the experiment and served as a control. Intestinal tumors were seen in groups 1 and 2, their incidence in group 1 (17%) being significantly lower than in group 2 (50%) (P < 0.05). Furthermore, the number of aberrant crypt foci/cm2 of colon in rats of group 1 at the termination of the experiment was significantly smaller than in group 2 (P < 0.01). BrdU labelling indices of S-phase mucosal cells in the colon of rats in group 1 were significantly lower than those in group 2 (3.9 +/- 3.1 vs. 9.1 +/- 4.5, P < 0.005). The present results suggest that the natural sesquiterpene contained in plants which have been used as oriental drugs, could be a promising chemopreventive agent for human intestinal neoplasia.

Animals↗
PubMed1994

Effect of docosahexaenoic acid on azoxymethane-induced colon carcinogenesis in rats.

The effect of intragastric gavage administration of docosahexaenoic acid (DHA) on azoxymethane (AOM)-induced colon carcinogenesis in rats was studied. Male F344 rats were treated s.c. with 15 mg/kg of AOM once a week for 2 weeks and were given either 0.7 ml of DHA or water intragastrically twice a week starting the day before the first carcinogen treatment. The number of crypt multiplicity (number of crypts/focus) of aberrant crypt foci (ACF) in the colon were measured after 4, 12, and 36 weeks. The numbers and average crypt multiplicities of ACF induced by AOM were significantly lower after 12 and 36 weeks in animals given DHA. DHA also reduced the incidence of spontaneous ACF in animals without carcinogen treatment. Colorectal tumor incidence and number of tumors per rat after 36 weeks were slightly, but not significantly, lower in the DHA-treated group. These results suggest that DHA slightly suppresses colon carcinogenesis, and a possibility that warrants further study.

Animals↗
PubMed1994

Monoamine oxidase B inhibitor enhances experimental carcinogenesis in rat colon induced by azoxymethane.

The effects of prolonged administration of the monoamine oxidase (MAO)-A inhibitor N-methyl-N-propargyl-3-(2,4-dichlorophenoxy)propylamine (clorgyline) and the MAO-B inhibitor N-methyl-N-2-propynyl-benzylamine (pargyline) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the norepinephrine (NE) concentration in the colon wall and the labeling index of colon mucosa were investigated in Wistar rats. Rats were treated s.c. with 7.4 mg/kg body weight of AOM once a week for 10 weeks, and also s.c. with 5 mg/kg body weight of clorgyline or 50 mg/kg body weight of pargyline in 0.9% NaCl until the end of the experiment. Treatment with pargyline significantly increased the incidence of colon tumors in week 35. However, it did not influence the histological appearance of the colon tumors or the histological types and depth of involvement of colon adenocarcinomas. Furthermore, it significantly increased the NE concentration in the colon wall and the labeling index of the colon mucosa during and after AOM-treatment. In contrast, clorgyline had no influence on the development or histological appearance of colon tumors. These findings indicate that the MAO-B inhibitor, but not the MAO-A inhibitor, enhanced colon carcinogenesis, and that its effect may be related to its effect in increasing the NE concentration in the colon wall and subsequently increasing the proliferation of colon epithelial cells.

Animals↗
PubMed1995

Suppression of azoxymethane-induced colonic aberrant crypt foci by dietary exposure to a novel synthesized retinoidal butenolide, 5-hydroxy-4-(2-phenyl-(E)ethenyl)-2(5H)-furanone, in rats.

The modifying effect of dietary exposure to a novel synthesized retinoidal butenolide, 5-hydroxy-4-(2-phenyl-(E)ethenyl)-2(5H)-furanone (KYN-5) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in male F344 rats. Animals were given weekly s.c. injections of AOM (15 mg/kg body wt.) for 3 weeks to induce ACF. These rats were fed diet containing 100 or 200 ppm KYN-54 for 5 weeks, starting 1 week before the first dosing of AOM. All rats were killed 2 weeks after the last AOM injection, to measure the number of ACF, ornithine decarboxylase (ODC) activity, mucosal polyamine level, and silver-stained nucleolar organizer regions protein (AgNORs) count per nucleus in the colon. In rats given AOM and KYN-54, the frequency of ACF/colon was significantly decreased compared with that in rats given AOM alone. ODC activity and polyamine levels, and the mean AgNORs number in the colon of rats given AOM and KYN-54 at both doses were also significantly lower than that of rats treated with AOM alone. These results provide further evidence that KYN-54 could be a chemopreventive agent against rat colon carcinogenesis.

4-Butyrolactone↗
PubMed1995

Enhancement by peptide histidine isoleucine of experimental carcinogenesis in the colon of rats induced by azoxymethane.

The effects of peptide histidine isoleucine (PHI) on the incidence and histology of colon tumors induced by azoxymethane (AOM), and on the labeling index of colon mucosa were investigated in Wistar rats. Rats received weekly s.c. injections of 7.4 mg/kg body weight of AOM for 10 weeks, and of 1.0 or 4.0 nmol/kg body weight of PHI until the end of the experiment in week 35. Administration of PHI at the higher, but not the lower dosage, significantly increased the incidence of colon tumors. PHI had no influence on the histology of colon tumors or adenocarcinomas. It also caused significant increase in the labeling index of colon epithelial cells. These findings indicate that PHI enhances colon carcinogenesis, and that its effect may be related to increasing proliferation of colon epithelial cells.

Adenocarcinoma↗
PubMed1995

Absence of p53 gene mutations in rat colon carcinomas induced by azoxymethane.

The K-ras and p53 genes are two of the most frequently mutated genes found in the human colonic tumors. Since azoxymethane (AOM) induced rat colonic neoplasms are similar to human colonic tumors in their histological features and proliferation characteristics, the rat has been used as an experimental model to study the pathogenesis of colon cancer in humans. Although the presence of K-ras point mutations has been reported in AOM induced rat colonic tumors, there are no reports describing the frequency for mutation of the p53 gene in these tumors. In this study, colon adenocarcinomas induced in rats by AOM were examined for the presence of point mutations in exons 5-8 of the p53 gene, using a combination of single strand conformation (SSCP) analysis, immunohistochemistry and direct DNA sequencing. SSCP analysis showed no differences in banding patterns between the normal mucosa and any of the 20 adenocarcinomas analyzed. Nuclear p53 immunoreactivity was absent in all tumors examined. Since p53 point mutations predominate in malignant colonic tumors, five adenocarcinomas with the greatest local invasiveness were analyzed by direct DNA sequencing of exons 5-8 of the p53 gene. Direct DNA sequencing did not reveal mutations in any of the adenocarcinomas analyzed, within the coding region of p53 gene that were sequenced. The results from the present study indicate that point mutations in the p53 gene, at least in the coding region (exons 5-8) are not involved in the development of colon cancer induced by AOM in the rat.

Adenocarcinoma↗
PubMed1996

Effects of diet and ethanol treatment on azoxymethane-induced liver and gastrointestinal neoplasia of male rats.

Epidemiological and animal studies have shown that diet and excessive alcohol consumption are major risk factors for liver and gastrointestinal cancers. This study investigated the effects of diet and alcohol consumption on azoxymethane (AOM)-induced liver and gastrointestinal neoplasia in male rats. Rats were infused intragastrically with control or ethanol-containing diets. After 35 days of dietary acclimatization, all rats received two intragastric infusions of AOM (15 mg/kg) separated by 1 week and then were maintained on standard rat food for 26 weeks. Results suggest that liver and duodenum are the major target organs when AOM is given orally and ethanol pre-exposure potentiates the AOM-induced hepatic and duodenal dysplasia.

Alcohol Drinking↗
PubMed1995

Identification and evaluation of the role of endogenous tyrosine kinases in azoxymethane induction of proliferative processes in the colonic mucosa of rats.

Although tyrosine kinases (Tyr-k) are known to play a role in regulating proliferation of normal, preneoplastic and neoplastic cells, little is known about the identity of different species of Tyr-k involved in this process. Utilizing a non-denaturing polyacrylamide gel electrophoresis system, in which the separated proteins from tissue extracts are assayed directly for Tyr-k, we attempted to identify the species of Tyr-k that may be involved in azoxymethane (AOM) induction of colonic mucosal ornithine decarboxylase (ODC) activity, an enzyme whose activity is known to rise in rapidly proliferating cells. We have observed that 5 days after a single injection of the colonic carcinogen AOM (20 mg/kg body wt) to 3-4-month old rats, a significant 230% rise in colonic mucosal proliferative activity (as evidenced by 5-bromo-2'-deoxyuridine (BrdU) immunoreactivity) was also accompanied by a 550% increase in ODC activity. This was also associated with a marked rise (140-240%) in the relative activity of Tyr-k of three mucosal proteins with MI of 165, 145 and 125 kDa. Since the molecular mass of one of the Tyr-k (165 kDa) corresponded to that of EGF-receptor (EGF-R), this led us to examine the role of EGF-R Tyr-k in AOM induction of colonic mucosal ODC. We observed that a 320% increase in mucosal ODC activity, 5 days after AOM injection, was accompanied by over 200% rise in Tyr-k activity of EGF-R. Daily injection of tyrphostin (300 micrograms/kg body wt.), a Tyr-k inhibitor with a higher specificity for EGF-R Tyr-k, significantly attenuated AOM-induced stimulation of both ODC and Tyr-k activity of EGF-R. Administration of AOM also stimulated the rate of synthesis and secretion of TGF-alpha in isolated colonocytes. In addition, the levels of TGF-alpha and its mRNA in the colonic mucosa were also found to be 100% and 250% higher, respectively, in AOM-treated rats when compared with the controls. We suggest that (a) activation of intrinsic Tyr-k of EGF-R is an important event in AOM induction of colonic mucosal proliferative processes, and (b) this activation is thought to be mediated by TGF-alpha through an autocrine mechanism.

Animals↗
PubMed2004

The modifying effect of Peucedanum japonicum, a herb in the Ryukyu Islands, on azoxymethane-induced colon preneoplastic lesions in male F344 rats.

The modifying effect of dietary Peucedanum japonicum (PJ), which is a traditional herb in the Ryukyu Islands and is an anti-oxidant, on azoxymethane (AOM)-induced rat colon carcinogenesis was examined. Male F344 rats were divided into six groups: rats in groups 1-4 were given subcutaneous injection of AOM (20 mg/kg body weight) once a week for 2 weeks. Rats in groups 2, 3 and 4 were fed the diets containing 0.2 and 1% PJ and 0.025% chlorogenic acid, respectively. We observed modification of the preneoplastic lesions of both aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCAC) in colon carcinogenesis, microscopically and immunohistochemically. The numbers of ACF consisting of more than four aberrant crypts per rat in groups 2 (3.2+/-1.7) and 3 (3.0+/-3.2) were significantly lower than that of group 1 (10.8+/-4.9; P<0.05, respectively). The mean number of BCAC in both groups 2 (0.88+/-0.48/cm2/rat) and 3 (0.81+/-0.34/cm2/rat) was significantly lower than that in group 1 (2.13+/-0.54/cm2/rat; P < 0.0001, respectively). In addition, proliferating cell nuclear antigen labeling indices in group 2 (10.98+/-2.03) and group 3 (9.85+/-2.62) were significantly lower than that in group 1 (14.87+/-3.93; P < 0.001 and P < 0.0001, respectively). These findings indicate that PJ inhibits both ACF formation and accumulation of beta-catenin, and that PJ also reduces the cell proliferation activity, suggesting that PJ may have chemopreventive potential for colon carcinogenesis.

Animals↗
PubMed2004

Modulatory influence of garlic and tomato on cyclooxygenase-2 activity, cell proliferation and apoptosis during azoxymethane induced colon carcinogenesis in rat.

Preventive intervention of colorectal cancer has become essential as a major portion of the population may develop the disease at some points during their lives. Diet and nutrition play an important role during this multistep colon carcinogenic process. Inhibitory activity of aqueous suspensions of garlic and tomato, individually and in combination, were tested on azoxymethane induced colon carcinogenesis in Sprague-Dawley rats. The effect was observed on aberrant crypt foci (ACF), the preneoplastic lesion. To investigate the mechanism of action of the agents used, cell proliferation and the level of apoptosis were determined and the expression of cyclooxygenase-2 (COX-2) protein was analyzed in the colon. Following treatment, significant inhibition of the level of cell proliferation (P<0.01 in garlic; P<0.001 in tomato and P<0.001 in combination treatment group with respect to the carcinogen control group), significant induction of apoptosis (P<0.01 in garlic treated; P<0.01 in tomato treated and P<0.001 in combination treatment group with respect to the carcinogen control group) and suppression of COX-2 expression among the treated groups resulted in significant reduction in the incidences of ACF (by 45.27% in garlic, 68.24% in tomato and 71.62% in combination treatment group). The preventive effect was better when the combination of garlic and tomato was administered in comparison to the individual treatment groups, suggesting the synergistic action of garlic and tomato.

Animals↗
PubMed2004

Preventive effects of extract of leaves of ginkgo (Ginkgo biloba) and its component bilobalide on azoxymethane-induced colonic aberrant crypt foci in rats.

The modifying effects of dietary feeding of extract of leaves of ginkgo (Ginkgo biloba) (EGb) and bilobalide isolated from EGb on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of EGb and bilobalide on proliferating cell nuclear antigen (PCNA) index in 'normal-appearing' crypts and activities of detoxifying enzymes of cytochrome P450 (CYP), glutathione S-transferase (GST) and quinine reductase (QR) activity in the liver. To induce ACF, rats were given two weekly subcutaneous injections of AOM (20 mg/kg body wt). They also received the experimental diets containing EGb (50 or 500 ppm) and bilobalide (15 or 150 ppm) for 4 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (106 +/- 10) at the end of the study (week 4). Dietary administration of EGb and bilobalide caused significant reduction in the frequency of ACF: 50 ppm EGb, 73 +/- 17 (31% reduction, P < 0.001); 500 ppm EGb, 56 +/- 13 (47% reduction, P < 0.001); 15 ppm bilobalide, 79 +/- 17 (25% reduction, P < 0.001); and 150 ppm bilobalide, 71 +/- 30 (33% reduction, P < 0.01). Immunohistochemically, EGb or bilobalide administration significantly lowered PCNA index in normal-appearing crypts. Feeding with EGb or bilobalide increased activities of CYP as well as GST and QR in the liver. These findings might suggest possible chemopreventive ability of EGb or bilobalide, through alterations in cryptal cell proliferation activity and drug metabolizing enzymes' activities, in colon tumorigenesis.

Administration, Oral↗
PubMed2004

Lactoferrin modifies apoptosis-related gene expression in the colon of the azoxymethane-treated rat.

Lactoferrin, an iron-binding glycoprotein, exhibits suppressive effects on development of azoxymethane (AOM)-induced tumors in the rat colon, but the mechanisms are largely unknown. In this study, we investigated the effect of lactoferrin on the gene expression of 10 apoptosis-related molecules in colon mucosa of AOM-treated rats during early and late stages of colon carcinogenesis by reverse transcription PCR. Here we document that a death-inducing receptor, Fas, and a pro-apoptotic Bcl-2 family member, Bid, are increased in the colon mucosa in proportion to decreases in AOM-induced aberrant crypt foci by lactoferrin. Similarly, increased expression of the pro-apoptotic Bcl-2 family member, Bax, was also observed in AOM-induced tumors in rats fed by lactoferrin. These results indicate that Fas and pro-apoptotic Bcl-2 members participate in the lactoferrin action and may contribute to suppressive effects on tumor development in the rat colon.

Administration, Oral↗
PubMed2005

The nonsteroidal anti-inflammatory drug, nabumetone, differentially inhibits beta-catenin signaling in the MIN mouse and azoxymethane-treated rat models of colon carcinogenesis.

The mechanisms through which beta-catenin signaling is inhibited during colorectal cancer chemoprevention by nonsteroidal anti-inflammatory agents is incompletely understood. We report that nabumetone decreased uninvolved intestinal mucosal beta-catenin levels in the MIN mouse with a concomitant increase in glycogen synthase kinase (GSK)-3beta levels, an enzyme that targets beta-catenin for destruction. However, in the azoxymethane-treated rat, where beta-catenin is frequently rendered GSK-3beta-insensitive, nabumetone failed to alter beta-catenin levels but did decrease beta-catenin nuclear localization and transcriptional activity as gauged by cyclin D1. In conclusion, we demonstrate that the differential mechanisms for beta-catenin suppression may be determined, at least partly, by GSK-3beta.

Animals↗
PubMed2005

Lack of enhancing effects of degraded lambda-carrageenan on the development of beta-catenin-accumulated crypts in male DBA/2J mice initiated with azoxymethane.

Effect of degraded lambda-carrageenan, which induces colitis in rodents, on the development of beta-catenin-accumulated crypts (BCAC) being putative precancer lesions of colon cancer was investigated in male DBA/2J mice initiated with azoxymethane (AOM). In a preliminary experiment, male DBA/2J mice among seven different strains (A/J, BALB/c, C3H/HeN, C57BL/6J, CBA/N, DBA/1J, and DBA/2J) of male mice were most sensitive to degraded lambda-carrageenan. Therefore, male DBA/2J mice were intraperitonially injected AOM (10 mg/kg body weight), and then 2% degraded lambda-carrageenan in drinking water for one or two weeks, starting one week after dosing of AOM. Thereafter animals were no further treated up to week 26. At week 26, the frequency of BCAC in the colonic mucosa was 12.50+/-2.46 in the AOM alone group, 11.30+/-3.50 in the AOM/degraded lambda-carrageenan (for one week) group, and 11.60+/-2.27 in the AOM/degraded lambda-carrageenan (for two weeks) group. The findings suggest that degraded lambda-carrageenan treatment for one or two weeks did not affect the occurrence of BCAC. Our results may indicate no enhancing or promoting effects of degraded lambda-carrageenan on colon carcinogenesis in mice initiated with AOM.

Animals↗
PubMed2005

Dietary artepillin C suppresses the formation of aberrant crypt foci induced by azoxymethane in mouse colon.

Artepillin C, a prenylated phenylpropanoid found specifically in Brazilian propolis, has been shown to be a bioavailable antioxidant. In this study, artepillin C was tested for colon cancer-preventing activity using azoxymethane-challenged ddY mice. Oral doses of 80 and 160 mg/kg body weight of propolis or 10mg/kg of artepillin C (equi-amounts to 160 mg propolis) reduced significantly the frequency of colonic aberrant crypt foci (ACF) by 39.2, 43.7 and 43.4%, respectively. In liver of the mice, glutathione S-transferase and NADPH:quinone reductase activity increased with the doses of propolis or artepillin C, and an antioxidant-responsive element (ARE) was found to be activated for binding DNA. Artepillin C is considered to suppress the formation of colonic ACF through the activation of ARE and induction of phase II enzymes in liver.

Animals↗
PubMed2006

Modifying effect of dietary sesaminol glucosides on the formation of azoxymethane-induced premalignant lesions of rat colon.

Sesame, which has been reported to have preventive effects against various disordered conditions, contains small quantities of lignans and several precursors to them such as sesaminol glucosides (SG). The lignans have the potent antioxidative activity and are suggested to have chemopreventive property. In the present study, we evaluated the modulating effect of SG on the development of colon precancerous lesions, aberrant crypt foci (ACF) and beta-catenin-accumulated crypts (BCAC), in the azoxymethane (AOM)-induced short-term model using male F344 rats. Dietary SG (500 ppm) significantly decreased the incidence of AOM-induced ACF when compared to the control (P<0.01). The incidences of AOM-induced BCAC in the SG-treated groups (250 or 500 ppm) were also significantly lower than that of the control group (P<0.01). Interestingly, administration of 500 ppm SG clearly decreased serum triglyceride level and mRNA expression of intestinal fatty acid-binding protein in the colonic mucosa, as compared to the control. These findings indicate that dietary SG inhibits AOM-induced carcinogenesis and suggest SG as a possible chemopreventive agent.

Animals↗