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PubMed2006

Long-term feeding of various fat diets modulates azoxymethane-induced colon carcinogenesis through Wnt/beta-catenin signaling in rats.

The Wnt signaling pathway plays an essential role in carcinogenesis, and the amount of fat intake and composition of dietary fatty acids are crucial factors for colon carcinogenesis. We investigated whether various dietary fats affected the Wnt signaling pathway of colon tumorigenesis in azoxymethane (AOM)-treated rats. Male Sprague-Dawley rats were given intraperitoneal injections of AOM and supplemented with 10% corn, olive, beef, and fish oil for 44 wk. Aberrant crypt foci (ACF) and tumors were examined at 12 and 44 wk. Normal appearing colon mucosal proliferation and apoptosis were evaluated by 5-bromo-2'-deoxyuridine (BrdU) incorporation and percentages of fragmented DNA, respectively. Expressions of beta-catenin, cyclin D(1), Wnt2, Wnt3, and Wnt5a of normal appearing colon mucosa were analyzed by Western blot analysis. Long-term dietary corn oil and beef tallow increased ACF, tumor incidence, and tumor numbers in AOM-treated rats. In contrast, both olive and fish oil inhibited them. Dietary corn oil and beef tallow increased BrdU incorporation and the expression of cytosolic beta-catenin and cyclin D(1) and decreased apoptosis in the colon mucosa. Expressions of Wnt2 and Wnt3 in rats fed with beef tallow and Wnt5a in rats fed with corn oil increased with or without AOM-treatment. BrdU-incorporated cells were often observed at the tops of crypts in rats fed with beef tallow, whereas this was not observed in rats fed with the other diet. Long-term high intake of corn oil and beef tallow enhanced cell proliferation through Wnt signaling and modulated the distribution of proliferating cells, which might contribute to promoting effects in colon tumorigenesis.

Animals↗
PubMed1999

Azoxymethane-induced fulminant hepatic failure in C57BL/6J mice: characterization of a new animal model.

Without transplantation, approximately 50-90% of all patients with fulminant hepatic failure (FHF) die. This poor outcome is due in part to the absence of an appropriate animal model, which would allow for a greater understanding of the pathophysiology of this syndrome. Given the reports of liver injury in humans and livestock fed cycad palm nuts on the island of Guam, we hypothesized that the active ingredient azoxymethane (AOM) could cause FHF. We therefore evaluated AOM in C57BL/6J mice. Histologically, we observed microvesicular steatosis 2 h, sinusoidal dilatation 4 h, and centrilobular necrosis 20 h after AOM administration, and transmission electron microscopy showed that this agent causes mitochondrial injury. FHF was associated with all four stages of encephalopathy, as well as by a prodromal period of decreased eating and drinking lasting approximately 15 h before the development of stage I encephalopathy (i.e., loss of scatter reflex). Late encephalopathy was associated with increased arterial ammonia, decreased serum glucose, and evidence of brain edema (astrocyte swelling). We show that AOM-induced FHF is highly reproducible, without evidence of lot-to-lot variability, and is dose dependent. These findings therefore suggest that AOM is an excellent agent for the study of FHF, as well as indicate that Guamanian FHF may be due to AOM found in unwashed cycad palm nuts.

Animals↗
PubMed1999

Azoxymethane-induced aberrant crypt foci and colorectal tumors in F344 rats: sequential analysis of growth.

Previous studies are consistent with the hypothesis that aberrant crypt foci (ACF) could be intermediate biomarkers in colorectal carcinogenesis. The present controlled experimental trial was performed to sequentially analyze ACF progression in rat colonic mucosa. F344 rats were administered 2-weekly doses of azoxymethane (15 mg/kg body weight, s.c.) and sacrificed 6, 12, 20, 30 and 36 weeks after the first carcinogen injection. Control groups of untreated rats were sacrificed at the same time points. The number of ACF per area, their multiplicity (number of crypts per focus), ACF frequency and multiplicity according to each colonic site, histology of ACF and macroscopic lesions were recorded. No ACF were found in control animals. In treated animals, the number of ACF per area and the multiplicity progressively and significantly increased throughout the study. ACF were prevalent in the mid colon. Lower frequencies were registered in the distal colon and rectum. ACF were rare in the proximal colon and cecum. By histology, ACF presented superficial and extensive hyperplasia. Tumors were found in the 30th and 36th week. Adenomas and well-differentiated adenocarcinomas were in the distal colon. All proximal neoplasms were signet ring cell carcinomas. In our study, ACF growing features and distribution are not correlated to adenoma and adenocarcinoma distribution. It is conceivable that signet ring cell carcinomas arising in the proximal colon, where ACF are rare, could present a different pathway of growth. The preneoplastic role of ACF and their function as intermediate biomarkers in colorectal carcinogenesis remain to be clarified.

Adenocarcinoma↗
PubMedDate not supplied

Suppression by verapamil of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in wistar rats.

BACKGROUND: The effects of combined administration of bombesin and verapamil hydrochloride (verapamil), a calcium channel blocker, on the incidence of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane (AOM) and the labeling index of intestinal cancers were investigated in male Wistar rats. METHODS: From the beginning of the experiment, rats were given 10 weekly subcutaneous injections of AOM (7.4 mg/kg body weight) and subcutaneous injections of bombesin (40 microg/kg body weight) every other day, and from week 16, intraperitoneal injections of verapamil (10 or 20 mg/kg body weight) every other day until the end fo the experiment in week 45. RESULTS: Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum. Although verapamil administered at either dose had little or no effect on the enhancement of intestinal carcinogenesis by bombesin or on the location, histologic type, depth of involvement, labeling index, apoptotic index or tumor vascularity of intestinal cancers, it significantly decreased the incidence of cancer metastasis. Verapamil also significantly decreased the incidence of lymphatic invasion of adenocarcinomas, which was enhanced by bombesin. CONCLUSION: These findings indicate that verapamil inhibits cancer metastasis through actions that do not affect the growth of intestinal cancers.

Adenocarcinoma↗
PubMed1992

Attenuation by the GABA receptor agonist baclofen of experimental carcinogenesis in rat colon by azoxymethane.

The effects of the gamma-amino-n-butyric acid (GABA)A receptor agonist muscimol, and the GABAB receptor agonist baclofen, on colon carcinogenesis induced by azoxymethane in Wistar rats were tested. Administration of either muscimol or baclofen had no influence on the incidence of colon tumors at week 30. However, almost all the colon tumors that developed in rats treated with baclofen were adenomas, whereas in the control group the tumors were mainly adenocarcinomas. In contrast, administration of muscimol did not affect the histological types of the colon tumors. These findings indicate that baclofen inhibits the growth of colon tumors via the GABAB receptor.

Adenocarcinoma↗
PubMedDate not supplied

Effects of quercetin and/or restraint stress on formation of aberrant crypt foci induced by azoxymethane in rat colons.

The present study examines the effect of dietary quercetin and/or restraint stress on the formation of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in the colon. Female F344 rats were divided into four groups. All animals were given intraperitoneal injections of AOM. The animals were fed a basal diet (group A, C), or a 2% quercetin-supplemented diet (group B, D). The animals were put individually to narrow wire cages for 1 h every day throughout the study to expose them to mild restraint stress (group C, D). At week 5, all the rats were killed and analyzed for ACF in the colon. The number of ACF increased significantly in the animals subjected to stress (p < 0.05). On the other hand, dietary quercetin significantly reduced the number of ACF in both the nonstress (p < 0.001) and stress groups (p < 0.05). These findings suggest that quercetin might have a potential as a chemopreventive drug for colon cancer despite stress.

Animals↗
PubMed1975

Dose response to a single injection of azoxymethane in rats. Induction of tumors in the gastrointestinal tract, auditory sebaceous glands, kidney, liver and preputial gland.

Male Fischer rats, 6 weeks old, were injected once with one of five doses of azoxymethane. There was a dose response to the carcinogen as determined by weight gain and tumor induction. Rats given the three highest doses developed tumors of the gastrointestinal tract, auditory sebaceous glands, kidney, liver, and preputial gland, whereas rats receiving the lowest doses had tumors mainly of the intestine. Chronic liver lesions in high-dose rats were cirrhosis with megalocytosis, mild fibrosis, nodular hepatocellular hyperplasia, and hyperplasia of bile ductules.

Adenocarcinoma↗
PubMed2004

Dietary corn oil promotes colon cancer by inhibiting mitochondria-dependent apoptosis in azoxymethane-treated rats.

How dietary corn oil is involved in colon carcinogenesis and cancer development is poorly understood. The aim of this study was to investigate whether long-term dietary corn oil promotes colon cancer by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis in azoxymethane (AOM)-treated rats. Male Sprague-Dawley rats were injected with AOM or with saline and fed on a basal diet or basal diet supplemented with 10% corn oil for 48 weeks. Colonic aberrant crypt foci (ACF) and tumors, including adenomas and carcinomas, were examined. Colonic apoptosis and cell proliferation were evaluated. Wild type (wt) p53 was analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. In addition, Bcl-2, Bcl-xL, Bax, and Bak localized in the mitochondria were detected. Long-term dietary corn oil increased ACF in AOM-treated rats at 12 weeks and promoted colon cancer invasion at 48 weeks. Cancer invasion was not observed in the AOM-treated rats without dietary corn oil, although colon adenomas and cancers were detected. Apoptosis was decreased and cell proliferation was increased in the AOM-treated rats with dietary corn oil, compared with the AOM-treated rats with dietary basal diet. In these rats, mitochondrial wt p53 was significantly inhibited through decreased mitochondrial localization of wt p53 and increased cytosolic p53, resulting in the upregulation of Bcl-2 and Bcl-xL and the downregulation of Bak in the mitochondria. Results suggest that long-term dietary corn oil promotes AOM-induced colon cancer development partly by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis.

Animals↗
PubMed2006

T cell deficiency leads to liver carcinogenesis in azoxymethane-treated rats.

There is an increasing amount of evidence suggesting that T cell deficiency contributes to tumor development. However, it is unclear whether T cell deficiency leads to liver and colon carcinogenesis. The aim of this study was to investigate the role of T cells on liver and colon carcinogenesis. Athymic F344/N Jcl-rnu/- (nu/nu) rats and euthymic F344/N Jcl-rnu/+(nu/+) rats were administered the carcinogen azoxymethane (AOM) at a dose of 15 mg/kg body wt once a week for 2 weeks. At 48 weeks after the second carcinogen treatment, the rats were sacrificed, and livers and colons were examined. Apoptosis and cell proliferation were evaluated by DNA fragmentation and proliferating cell nuclear antigen assays, respectively. Wild-type p53 and members of the Jun and Fos oncogene families were detected by Western blotting. AOM treatment induced 100% liver tumor and 63.6% colon tumor incidence in T cell-deficient nu/nu rats, compared with 0% and 38.5% incidence in nu/+ rats. T cell deficiency promoted the inhibitory action of AOM on apoptosis in both liver and colon at 48 weeks. In contrast, T cell deficiency increased cell proliferation after AOM treatment in both tissues. Wild-type p53 was reduced in both tissues of T cell-deficient rats. AOM treatment induced c-Jun and c-Fos expressions in the liver but increased only Fos B in the colon, whereas T cell deficiency enhanced c-Jun overexpression in the liver. These results suggest that T cell deficiency leads to liver carcinogenesis partly by a reduction in wild-type p53 and increasing c-Jun expression in AOM-treated rats.

Animals↗
PubMed1978

The cytochemical demonstration of beta-glucuronidase in colon neoplasms of rats exposed to azoxymethane.

Colon tumors induced with azoxymethane in male Fischer rats were cytochemically analyzed for beta-glucuronidase using naphthol AS-B1 glucuronide (6-bromo-2-hydroxy-3-naphthoyl-O-anisidine) as a substrate and hexazonium pararosanin as a diazo reagent. This method effectively localizes the bulk of beta-glucuronidase in the surface epithelium, the lamina propria and in the endothelial cells of the lymphoid sinuses and postcapillary venules. Polypoid lesions, adenocarcinomas and mucinous adenocarcinomas show no difference in the amount or in the localization of beta-glucuronidase; however, mucinous adenocarcinomas show a slight increase in the amount of beta-glucuronidase. The few tumors that did metastasize to lymph nodes did not show any difference in their enzyme patterns. Intestinal crypts that show a change in size and shape have a definite increase in beta-glucuronidase activity. An increase in the activity of this enzyme can also be seen in well defined neoplasms as opposed to normal areas of the colon.

Adenocarcinoma↗
PubMed1999

Colon cancer is induced by a single low dose of azoxymethane in fasted-refed rats.

We reported previously that fasting-refeeding enhanced the growth of preneoplastic lesions in the colon of rats induced by 20 mg/kg of azoxymethane (AOM). Here we studied whether fasting-refeeding could also affect 1) the induction of colon cancer by the same dose of AOM and 2) the induction of foci by lower doses of AOM that do not induce foci in fully fed rats. Fully fed and fasted-refed rats were given AOM by single subcutaneous injection, and the development of foci or tumors was evaluated three months or one year later. The results of the long-term carcinogenesis experiments showed that the total incidence of tumors was increased in the fasted-refed rats. Moreover, although fully fed rats developed foci only when injected with 7.5, 10, or 20 mg/kg of the carcinogen, a significant number of foci were also induced by 5 mg/kg in fasted-refed rats. The crypt multiplicity of foci was also higher when rats were exposed to fasting-refeeding, even when the number of foci was unchanged. These data suggest that growth perturbations induced by fasting-refeeding lead to the development of preneoplastic lesions with doses of AOM too low to trigger foci in fully fed rats and produce enhanced sensitivity to the development of intestinal tumors.

Animals↗
PubMed2000

Inhibition of azoxymethane-induced colon cancer by orange juice.

Previous research has shown that hesperidin, a flavanone glycoside in orange juice, inhibits colon carcinogenesis and that feeding double-strength orange juice delays the onset of chemically induced mammary cancer in rats. This study determined whether feeding single-strength, pasteurized orange juice would inhibit azoxymethane (AOM)-induced colon cancer in male Fischer 344 rats. Colon cancer was initiated by injecting AOM (15 mg/kg body wt) at 22 and 29 days of age. One week after the second AOM injection, orange juice replaced drinking water for the experimental group (n = 30). The rats were killed 28 weeks later, and tumors were removed for histological analysis. Feeding orange juice reduced tumor incidence by 22% (p < 0.05). Tumor reduction was associated with a decreased labeling index and proliferation zone in the colonic mucosa. Hesperidin, other flavonoids, limonin 17-beta-D-glucopyranoside, and other limonoid glucosides are potential chemopreventive agents in orange juice that could account for the decreased colon tumorigenesis associated with feeding orange juice.

Animals↗
PubMed2001

Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2'-deoxyguanosine levels in the Fischer 344 rat.

This study examined the effects of lyophilized black raspberries (BRB) on azoxymethane (AOM)-induced aberrant crypt foci (ACF), colon tumors, and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in male Fischer 344 rats. AOM was injected (15 mg/kg body wt i.p.) once per week for 2 wk. At 24 h after the final injection, AOM-treated rats began consuming diets containing 0%, 2.5%, 5%, or 10% (wt/wt) BRB. Vehicle controls received 5% BRB or diet only. Rats were sacrificed after 9 and 33 wk of BRB feeding for ACF enumeration and tumor analysis. ACF multiplicity decreased 36%, 24%, and 21% (P < 0.01 for all groups) in the 2.5%, 5%, and 10% BRB groups, respectively, relative to the AOM-only group. Total tumor multiplicity declined 42%, 45%, and 71% (P < 0.05 for all groups). Although not significant, a decrease in tumor burden (28%, 42%, and 75%) was observed in all BRB groups. Adenocarcinoma multiplicity decreased 28%, 35%, and 80% (P < 0.01) in the same treatment groups. Urinary 8-OHdG levels were reduced by 73%, 81%, and 83% (P < 0.01 for all groups). These results indicate that BRB inhibit several measures of AOM-induced colon carcinogenesis and modulate an important marker of oxidative stress in the Fischer 344 rat.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Consumption of black beans and navy beans (Phaseolus vulgaris) reduced azoxymethane-induced colon cancer in rats.

Beans (Phaseolus vulgaris) are an important food staple in many traditional diets. There is limited evidence to suggest an inverse relationship between bean consumption and colon cancer. The objective of this study was to determine whether consumption of black beans and/or navy beans would reduce colon carcinogenesis in rats. Rats were fed a modified AIN-93G diet (control) or diets containing 75% black beans or 75% navy beans for 4 wk, and then colon cancer was initiated by administration of two injections of azoxymethane 1 wk apart. At 31 wk after the second injection, the incidence of colon adenocarcinomas was significantly lower (P < 0.05) in rats fed the black bean (9%) and navy bean (14%) diets than in rats fed the control diet (36%). Total tumor multiplicity was also significantly lower in rats fed the black bean (1.1) and navy bean (1.0) diets than in rats fed the control diet (2.2). The 44-75% reduction in colon carcinogenesis in rats fed beans was attributed to 1) more controlled appetites, leading to significantly less body fat, and 2) much greater concentrations of butyrate in the distal colon. It was concluded that eating black beans and navy beans significantly lowered colon cancer incidence and multiplicity.

Adenocarcinoma↗
PubMed2003

Effects of green tea and high-fat diet on arachidonic acid metabolism and aberrant crypt foci formation in an azoxymethane-induced colon carcinogenesis mouse model.

Excessive fat consumption is a risk factor for colon carcinogenesis, and green tea consumption may reduce the risk of colon and other cancers. The current study was designed to investigate the effects of green tea and a high-fat diet on arachidonic acid metabolism and aberrant crypt foci formation in an azoxymethane (AOM)-induced colon carcinogenesis mouse model. We also determined whether green tea consumption altered the size of regional fat pads. CF-1 female mice were maintained on either a high-fat (20% corn oil) or a low-fat (5% corn oil) diet. AOM was given subcutaneous at a dose of 7.5 mg/kg body weight at 6 wk and then a dose of 10 mg/kg at 7 wk of age. Two weeks after the second AOM injection, 0.6% green tea (6 mg tea solids/ml) was given as the drinking fluid and continued for 10 wk until the experiment was terminated. In the AOM-treated mice not receiving green tea, the high-fat diet significantly enhanced colonic levels of 5-lipoxygenase, leukotriene A4 hydrolase, and leukotriene B4, but it did not significantly alter prostaglandin E2 levels and aberrant crypt foci formation. In AOM-treated mice on the high-fat diet, green tea significantly decreased colonic levels of cytosolic phospholipase A2, 5-lipoxygenase, and leukotriene B4; green tea treatment also decreased the number of aberrant crypt foci (P < 0.05). The weights of parametrial and retroperitoneal fat pads were increased by the high-fat diet and decreased by green tea treatment. The current results indicate that green tea consumption and dietary fat modulate 5-lipoxygenase-dependent pathway of arachidonic acid metabolism during AOM-induced colon carcinogenesis. Green tea inhibits ACF formation in mice on a high corn oil diet, suggesting its possible inhibitory effect on colon carcinogenesis in populations such as those in Western countries that consume high amounts of fat.

Adipose Tissue↗
PubMed2004

Dietary iron promotes azoxymethane-induced colon tumors in mice.

There is accumulating evidence that high levels of dietary iron may play a role in colon carcinogenesis. We used a mouse model to investigate the impact of elevated dietary iron on incidence of aberrant crypt foci (ACF; a preneoplastic lesion) on tumor formation and on induction of oxidative stress. A/J mice were injected intraperitoneally, once a week for 6 weeks, with the colonotropic carcinogen, azoxymethane (AOM) or saline (vehicle controls). Following AOM or saline treatments, mice were placed on diets of high (3,000 ppm) and low (30 ppm) iron. Mice in each treatment group were sacrificed at 6 and 10 weeks following the final injection with AOM or saline. Colons were removed for subsequent histopathological analysis, which revealed average increases of 4.6 +- 1.3 vs. 10.4 +- 2.5 total tumors at 6 weeks and 30.75 +- 2.7 vs. 41.5 +- 4.4 total tumors at 10 weeks per AOM-treated mouse on low- and high-iron diets, respectively. There were no significant differences in incidence of ACF attributable to iron, although there was a trend toward greater crypt multiplicity per focus in mice on high-iron diets. Notably, no tumors were observed in mice receiving vehicle control injections in place of carcinogen, regardless of the level of dietary iron. These data suggest that iron exerts its effect at the stage of tumor promotion, but is not sufficient to initiate tumor formation. To learn more about mechanisms by which iron promotes tumor growth, colons were assayed for several biomarkers of oxidative stress [BOS; total F2-isoprostanes (F2-IsoPs), 15-F2t-isoprostanes (8-IsoPGF2s), Isofurans (IsoFs), and 8-hydroxyguanosines (8-OH[d]Gs)], as well as iron absorption, programmed cell death, and cellular proliferation. Elevated PCNA and TUNEL staining of the colon epithelium revealed hyperproliferative and apoptotic responses to iron, while no significant differences between iron groups were observed in each of the BOS that were assayed. Our results suggest that, following carcinogen exposure, elevated dietary iron promotes the growth of tumors with altered cellular homeostasis through a mechanism that is independent of oxidative stress.

Animals↗
PubMed2004

Extract of Kurosu, a vinegar from unpolished rice, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats.

The modifying effects of administering an ethyl acetate extract of Kurosu (EK), a vinegar made from unpolished rice, in drinking water on the development of azoxymethane (AOM)-induced colon carcinogenesis were investigated in male F344 rats. Animals were given 2 weekly subcutaneous injections of AOM (20 mg/kg body weight). They also received drinking water containing 0%, 0.05%, or 0.1% EK for 35 wk, starting 1 wk after the last dosing of AOM. EK administration significantly inhibited the incidence and multiplicity of colon adenocarcinoma (P < 0.05), compared with those in the AOM alone group. These findings suggest that EK may be effective for inhibiting colon carcinogenesis.

Acetic Acid↗
PubMed2006

Carbohydrate digestibility predicts colon carcinogenesis in azoxymethane-treated rats.

The purpose of this study was to compare the effect of carbohydrate structure and digestibility on azoxymethane (AOM)-induced colon carcinogenesis. Five groups of male Fischer 344 rats each comprising 30 animals were injected with AOM and fed a high-fat diet with 15% of various carbohydrates. The carbohydrate sources used were sucrose, cornstarch (a linear starch, reference group), potato starch (a branched starch), a short-chained oligofructose (Raftilose), and a long-chained inulin-type fructan (Raftiline). An interim sacrifice was performed after 9 wk to investigate markers of carbohydrate digestibility, including caecal fermentation (caecum weight and pH) and glucose and lipid metabolism [glucose, fructoseamine, HbA1c, triglycerides, and insulin-like growth factor (IGF) 1]. In addition potential early predictors of carcinogenicity [cell proliferation and aberrant crypt foci (ACF)] at 9 wk and their correlation to colon cancer risk after 32 wk were investigated. Tumor incidence was significantly reduced in animals fed oligofructose, and the number of tumors per animal was significantly reduced in animals fed inulin and oligofructose at 32 wk after AOM induction compared to the reference group fed sucrose. Increased caecum weight and decreased caecal pH were seen in groups fed oligofructose, inulin, and potato starch. Plasma triglyceride was decreased in rats fed oligofructose and inulin. Cell proliferation was increased in the proximal colon of rats fed sucrose, oligofructose, and inulin, and the number of cells per crypt decreased in rats fed oligofructose and inulin. The total number of ACF's was unaffected by treatment, and the size and multiplicity of ACF was unrelated to tumor development. It was concluded that less digestible carbohydrates with an early effect on caecum fermentation and plasma triglyceride decreased subsequent tumor incidence and multiplicity. This was unrelated to ACF, cell proliferation, and other markers of glucose and lipid metabolism.

Animals↗