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PubMed2001

Profiling proteins from azoxymethane-induced colon tumors at the molecular level by matrix-assisted laser desorption/ionization mass spectrometry.

New developments in mass spectrometry allow for the profiling of the major proteomic content of fresh tissue sections. Briefly, fresh tissue sections are sampled and blotted onto a polyethylene membrane for protein transfer and then subsequently analyzed by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). Using this technology, we have compared the protein expression of normal and cancerous mouse colon tissue obtained from the same animal. By difference, several protein signals specific to cancerous tissue were observed. A protein extract obtained from the tumors was fractionated by high-performance liquid chromatography and the individual fractions analyzed by MALDI-MS. The fractions containing the targeted proteins were subjected to trypsin digestion. The resulting tryptic peptides were sequenced by tandem mass spectrometry, and based on the recovered partial amino acid sequences, three of the tumor specific protein markers were identified as calgranulin A (S100A8), calgranulin B (S100A9) and calgizzarin (S100A11).

Animals↗
PubMed2002

Inhibitory Effects of Chlorogenic Acid on Azoxymethane-induced Colon Carcinogenesis in Male F344 Rats.

Modifying effects of chlorogenic acid (CA) on carcinogen-induced large bowel carcinogenesis was examined in rats. A total of 150 male F344 rats, 4 weeks old, were divided into 5 groups. At 6 weeks of age, groups 1-3 were given subcutaneous injections of AOM (15 mg/kg body weight) once a week for three weeks. Group 2 was given the diet mixed with CA at the dose of 250 ppm during the initiation phase (5 weeks), and group 3 was exposed to the same diet during the post-initiation phase (32 weeks). Group 4 received the diet with CA throughout the experiment. Group 5 was maintained on the basal diet alone and served as a control. At the termination of the experiment (36 weeks after the start), the incidence of colon tumors in group 2 and 3 demonstrated a tendency for decrease as compared with group 1 although this did not attain significance At this time, the multiplicity of colon tumors of group 2 was significantly smaller than in group 1. In this study, the anti-proliferating cell nuclear antigen (PCNA) indices for non-neoplastic cells of the colon mucosae in groups 2 and 3 were also smaller than in group 1. The data suggest that CA has chemopreventive potential against colon carcinogenesis in rats like that showen in a hamster model with use of methylazoxymethanol acetate.

Journal Article↗
PubMed2004

Aspirin inhibits endothelial nitric oxide synthase (eNOS) and Flk-1 (vascular endothelial growth factor receptor-2) prior to rat colon tumour development.

Formation of blood vessels is a fundamental element in the control of tumour growth in which vascular endothelial growth factor (VEGF) and nitric oxide (NO) have been demonstrated to be involved. Our aim was to analyse whether changes in the expression of endothelial NO synthase (eNOS) and VEGF in colonic tissue could be detected early and even before the identification of colon tumour-associated morphological modifications in azoxymethane-treated rats. We studied further whether aspirin treatment changed these parameters. An increased expression of both eNOS and VEGF in colonic tissue from azoxymethane-treated rats compared with that from control rats was found. Aspirin treatment (10 mg/kg of body weight per day) reduced eNOS expression, but failed to modify the expression of VEGF in the colonic tissue of azoxymethane-treated rats. No evidence of aberrant crypt formation or changes in the number of blood vessels were observed in the colon of any of the animals studied. Expression of the VEGF receptor Flk-1, but not Flt-1, was increased in colonic tissue of azoxymethane-treated rats compared with control rats. The expression of Flk-1 was mainly localized in the epithelial cells, particularly in the lower part of the crypt. Aspirin treatment reduced Flk-1 expression in both control and azoxymethane-treated rats. Caspase-3 activity, which has been considered as an apoptotic index, was almost undetectable in azoxymethane-treated rats. Aspirin treatment stimulated caspase-3 activity. Overexpression of eNOS, VEGF and its receptor Flk-1 occurred early after azoxymethane administration in rat colonic tissue, even before morphological changes associated with tumour generation were observed, and aspirin prevented the overexpression of both eNOS and VEGF receptor Flk-1.

Animals↗
PubMed1986

Effect of warfarin on formation and growth of pre-neoplastic lesions in chemically induced colorectal cancer in the rat.

Anticoagulant drugs are known to have an effect on tumour growth. However, the mechanisms by which they act are poorly understood, and have therefore been investigated in this study. Wistar rats were given eight weekly subcutaneous injections of azoxymethane, at a dose of 10 mg kg-1 week-1. Following this they were randomized into two groups: a control group, which received no further treatment, and a warfarin treated group, which received warfarin at 'non-therapeutic' doses in their drinking water, for a further 8 weeks. Pairs of rats from each group were killed at 5-weekly intervals from 10 to 35 weeks after the first azoxymethane injection. At 40 weeks all remaining rats were killed. Samples of colonic mucosa from the descending colon and rectum were taken for scanning electron microscopy. The number of microadenomas per low power field was determined in both groups at each time interval. Tumour incidence and distribution were noted in animals killed at 40 weeks. The median number of microadenomas was significantly lower in warfarin treated animals than in controls at all time intervals. Tumour number was also significantly decreased by warfarin treatment (27 in azoxymethane treated animals, 10 in animals receiving azoxymethane and warfarin, P less than 0.05). The distribution of tumours along the colon was similar to that seen previously, following 12 weeks of azoxymethane. These effects occurred despite the non-concurrent administration of azoxymethane and warfarin.

Adenoma↗
PubMed1985

Organ-specific carcinogenesis in rats by methyl- and ethylazoxyalkanes.

Azoxyalkanes are isomeric with nitrosodialkylamines and could be similar in their biochemical and biological actions. To compare the structure-activity relations in the two series, the tumorigenic activities of four azoxyalkanes, azoxymethane, azoxyethane, Z-ethyl-O,N,N-azoxymethane, and Z-methyl-O,N,N-azoxyethane, were compared in male F344 rats by p.o. administration of 0.54 mM and 0.135 mM solutions in drinking water. In most cases, treatment lasted 30 weeks, but at the higher dose of the two ethylazoxy compounds, 24 weeks of treatment were sufficient. Most of the animals died with tumors that could be attributed to the treatments. The two ethylazoxy compounds caused much earlier death from tumors than the corresponding methylazoxy compounds. All four compounds induced a high incidence of liver neoplasms, which were mainly hepatocellular; the two ethylazoxy compounds also induced a large number of hemangiosarcomas in the liver. At both dose levels, azoxyethane induced tumors of the esophagus and nasal cavity, tumors that were not seen in any other group. Other tumors appearing in significant incidence were in the colon and ileum, induced by azoxymethane and Z-ethyl-O,N,N-azoxymethane, and kidney tumors induced by azoxymethane and Z-methyl-O,N,N-azoxyethane. In F344 rats, azoxyethane was similar in carcinogenic activity to its isomer nitrosodiethylamine, whereas azoxymethane was much less potent than nitrosodimethylamine and induced quite different tumors. These results suggest that the biochemical activation of azoxylkanes is different from the analogous nitrosodialkylamines.

Animals↗
PubMed1987

Effect of hypothermia on intestinal adaptation and carcinogenesis in the rat.

Postoperative hyperplasia enhances experimental intestinal carcinogenesis, but the effects of nonsurgical adaptation are uncertain. The tropic and tumour-promoting potentials of moderate hypothermia were tested in two groups of male Sprague-Dawley rats housed at 10 degrees C for 30 weeks. One group (n = 10) received a 6-week course of azoxymethane (total dose 90 mg kg-1). The second group (n = 7) acted as hypothermic controls. Another 2 groups maintained at 22 degrees C received azoxymethane (n = 15) or served as normothermic controls (n = 15). Overall food intake was 42% higher in the hypothermic groups, yet at sacrifice mean body weight was 13% lower (P less than 0.01). Hypothermia and azoxymethane combined to produce the following increases in crypt cell production rate (CCPR), as determined stathmokinetically: duodenum 170%, jejunum 172%, ileum 74%, proximal colon 227% (P = 0.05-0.01). Independently hypothermia had no effect, but azoxymethane produced 76-156% increases in CCPR throughout the large intestine. Although hypothermia did not affect overall tumour yield, the mean diameter of proximal colonic tumours was increased by 65% (P less than 0.05). In rats receiving azoxymethane, hypothermia stimulates cell proliferation in the small bowel as well as in the proximal colon, where it has a correspondingly mild cocarcinogenic effect.

Adaptation, Biological↗
PubMed1989

Effects of the experimental chemopreventative agent, glucarate, on intestinal carcinogenesis in rats.

Dietary calcium glucarate was previously shown to protect effectively against chemically-induced mammary, lung, liver and skin carcinogenesis in rodents, whereas the negative dietary calcium control, calcium gluconate, had no effect. In the present study the chemopreventative activity of dietary calcium glucarate was evaluated in the azoxymethane intestinal carcinogenesis model using the Fischer strain rat. The protocol limited the duration of azoxymethane treatment to 3 weeks to permit the evaluation of the separate effects of glucarate on the initiation and promotion phases. Control rats, treated with azoxymethane and maintained on a low fat chow diet throughout the 32-week experiment had an intestinal adenocarcinoma incidence of 55%, with an equal incidence of 27.7% in the small and large intestines. There was no significant difference between this control group and a negative calcium control group fed 128 mmol/kg chow of calcium as calcium gluconate. In contrast to these two control groups, supplementation of the diet of azoxymethane-treated rats with 128 mmol/kg diet of calcium glucarate during both the initiation and promotion phases significantly inhibited the overall induction of adenocarcinomas in the intestine, the incidence in the entire intestine and in the small and large intestines being 11.8, 5.8 and 5.8%, respectively. When fed only during the initiation phase, the inhibition again was statistically significant, the corresponding values being 11.8%, 5.8 and 5.8%. When calcium glucarate was fed during the promotion phase, a statistically significant inhibition of adenocarcinoma induction was observed only in the colon where the incidence was 5.5%. Weight gain was similar in all groups. These and related data indicate that dietary glucarate exerts a significant inhibitory effect on azoxymethane-induced intestinal and in particular colon carcinogenesis in the rat, decreasing their incidence and size and reducing their metastic potential.

Animals↗
PubMed2006

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling.

Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

Animals↗
PubMed1993

The influence of the interaction of sutures with the mucosa on tumour formation at colonic anastomoses in rats.

In order to explore the respective role of wound healing and suture material on metachronous carcinogenesis at colonic lines in rats, tumour yield was studied after the administration of a chemical carcinogen (azoxymethane) at the moment that in one group of rats most of the suture material was still present and crypt cell proliferation elevated, while in another group, no more suture material was present and crypt cell proliferation rate (CCPR) normalized at the anastomotic site. Azoxymethane (15 mg/kg/week, s.c., during 6 weeks) was administered in male Sprague-Dawley rats (n = 105) 8 weeks after the creation of an anastomosis in the ascending and descending colon with either stainless steel sutures (group A, n = 30) or fast-absorption Vicryl (Vicryl Rapide, group B, n = 30). A control group (group C, n = 30) underwent a sham laparotomy before the administration of azoxymethane, while the animals of a fourth group (group D, n = 15) were not operated upon and received no azoxymethane. Twenty-six weeks after the first injection of azoxymethane there was no significant difference in the total colorectal tumour yield in the three operated groups (A, B, C), but a significantly greater proportion of anastomotic tumours (28/68 vs. 13/88, p < 0.01) and more anastomotic tumours per rat (28/23 vs. 13/28, p = 0.01) as well as more rats with anastomotic tumours (16/23 vs. 11/28, p = 0.04) were found in the steel-sutured group (A), compared with the control group (C).(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1985

Effect of deoxycholic acid on the tumour incidence, distribution, and receptor status of colorectal cancer in the rat model.

It has previously been observed that 25% of human colorectal cancers contain specific receptors to deoxycholic acid (DCA). In the present study, the effect of intrarectal instillation of DCA on tumour number, distribution, size, and DCA receptor status was measured in rats receiving the colorectal carcinogen, azoxymethane. Rats treated with azoxymethane and intrarectal DCA developed significantly more colorectal cancers than rats receiving azoxymethane and intrarectal saline (median 11.5, range 8-17 vs. median 6.0, range 3-9 tumours/rat, respectively, p less than 0.01). This reflected a significantly higher number of tumours in the distal colon of the DCA-treated group (median 8.0, range 5-10 tumours/rat) compared to the saline-treated group (p less than 0.01). In those rats receiving DCA and azoxymethane, 5 of 12 tumours tested were found to be DCA receptor-positive, compared with only 1 of 11 in the saline and azoxymethane group. These results confirm the belief that DCA acts as a tumour promoter, and suggest a possible role for DCA receptors.

Animals↗
PubMed1987

Carcinogenesis by nitrosodialkylamines and azoxyalkanes given by gavage to rats and hamsters.

The carcinogenic effects of three nitrosamines, nitrosodimethylamine (NDMA), nitrosodiethylamine (NDEA), and nitrosomethylethylamine (NMEA), and two azoxyalkanes, azoxymethane and azoxyethane, have been compared by administration by gavage of multiple equimolar doses to F344 rats and Syrian golden hamsters. NDMA and azoxymethane were severely toxic to hamsters, requiring the use of lower dose rates. In hamsters, the most commonly observed tumors were hepatocellular, cholangiocellular, and vascular tumors of the liver, but azoxyethane, NMEA, NDMA, and NDEA also induced tumors of the nasal mucosa, and azoxymethane induced tumors of the colon. In hamsters, NDEA and azoxyethane were less potent carcinogens than the corresponding methyl compounds, NDMA and azoxymethane. In contrast, in rats the two ethyl compounds were more potent than the corresponding methyl compounds, and NMEA was intermediate in potency. In rats, all three nitrosamines commonly induced liver tumors, mostly hepatocellular, but few liver tumors were induced by the two azoxyalkanes. Instead, azoxymethane induced colon tumors and azoxyethane induced tumors of the nasal mucosa. When given by gavage, NDMA induced a high incidence of mesenchymal tumors of the kidney and alveolar-bronchiolar tumors of the lungs as well as liver tumors.

Administration, Oral↗
PubMed1991

The effects of intracolonic EGF on mucosal growth and experimental carcinogenesis.

Although intra-luminal epidermal growth factor (EGF) may stimulate cell proliferation in the upper gastrointestinal tract, its role in the large bowel has not been established. We have therefore studied the effect of intra-rectal EGF administration on both normal growth and carcinogenesis in the rat colon. Colonic cancer was induced in rats with azoxymethane (10 mg kg-1 week-1 for 12 weeks s.c.) and controls dosed with saline. In each group, animals were randomised to receive EGF (12 nM, 0.8 nM or saline control) in 0.5 ml saline via a rectal tube daily for 24 weeks. At this time, crypt cell production rates (CCPRs) were determined at two sites in the colon: one of maximal and another of minimal exposure to EGF (5 cm and 10 cm from the anal margin respectively). No effects of EGF were seen at 10 cm. The lower dose of EGF gave CCPRs that mirrored the control values. The higher dose of EGF in the animals not treated with azoxymethane stimulated mucosal growth. Azoxymethane increased in CCPR, but this was suppressed by the high dose of EGF. These results suggest that (1) luminal EGF and azoxymethane independently increase the colonic CCPR and their combined effect is not synergistic but antagonistic; (2) EGF may have a role in normal epithelial growth, but does not potentiate colonic carcinogenesis in this model.

Animals↗
PubMed1997

Dietary fat and fiber modulate the effect of carcinogen on colonic protein kinase C lambda expression in rats.

To elucidate the mechanisms by which dietary factors influence the risk of colon cancer, we investigated the effect of select dietary fats and fibers on atypical protein kinase C (PKC) lambda expression. Azoxymethane- and saline (control)-injected rats were fed diets containing either corn oil or fish oil (15 g/100 g) and either cellulose or pectin (6 g/100 g) and killed at two time points (15 and 37 wk) in a 2 x 2 x 2 x 2 factorial design. Colonic PKC lambda protein and mRNA levels were determined using immunoblotting and relative competitive polymerase chain reaction, respectively. Azoxymethane suppressed cytosolic PKC lambda protein levels compared with the saline controls at both time points, and this suppression was partially blocked by fish oil feeding at 15 wk and pectin at 37 wk. Also, at 15 wk, azoxymethane-injected rats fed corn oil had higher levels of membrane PKC lambda relative to the other treatment groups. Overall, expression of PKC lambda mRNA was not correlated with differences in the respective isozyme protein levels. Therefore, the chemopreventive effects of dietary fish oil and pectin are associated with the blockage of azoxymethane-induced alterations in colonic PKC lambda protein expression.

Animals↗
PubMed2003

The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development.

BACKGROUND: During development, the homeobox gene Cdx2 exerts a homeotic function, providing the positional information necessary for correct specification of the midgut endoderm. This is illustrated by the non-neoplastic gastric-type heteroplasias present at birth in the pericaecal region of Cdx2(+/-) mice. Furthermore, intestinal expression of Cdx2 continues throughout life but diminishes in colorectal cancers compared with adjacent normal tissue, suggesting a role in tumorigenesis. AIM: To investigate the consequence of altered Cdx2 expression on colon tumour initiation and/or progression. METHODS: Heterozygous Cdx2(+/-) mice were analysed for spontaneous malignant tumours and for tumour development after treatment with a DNA mutagen, azoxymethane. RESULTS: Cdx2(+/-) mice did not spontaneously develop malignant tumours. After azoxymethane treatment, the gastric-like heteroplasias in the pericaecal region did not evolve into cancer indicating that they are not precancerous lesions. However, azoxymethane treated Cdx2(+/-) mice developed tumours specifically in the distal colon 12 weeks after azoxymethane treatment whereas no tumours were found in wild-type littermates at this stage. Histopathological and molecular analyses indicated that these tumours were invasive adenocarcinomas that recapitulated the malignant sequence observed in the majority of sporadic colorectal cancers in human. In addition, we found that the colonic epithelium was less sensitive to radiation induced apoptosis in Cdx2(+/-) than in wild-type mice. CONCLUSION: This study provides the first experimental evidence that Cdx2 is a tumour suppressor gene involved in cancer progression in the distal colon. This action in adults is functionally and geographically distinct from its homeotic role during gut development.

Adenocarcinoma↗
PubMed1998

Dietary quercetin, immune functions and colonic carcinogenesis in rats.

Rats fed 100 mg/kg quercetin (QUE) daily for 7 weeks had significantly enhanced natural killer cell activity compared to their vehicle (VEH)-fed control. In contrast, rats fed 100 mg/kg QUE and treated with the colon carcinogen, azoxymethane had significantly reduced natural killer cell activity compared to their VEH-fed azoxymethane-treated control. There was no significant difference in natural killer cell activity between the two control groups. Antibody production and delayed-type hypersensitivity were not altered by QUE feeding in any treatment group. In vitro exposure of splenic natural killer cells to 1mM QUE significantly decreased natural killer cell cytotoxicity. Lower QUE concentrations produced a non-significant reduction in natural killer cell activity that was restored to control values at 1 x 10(-13)M QUE. The distribution, multiplicity and total number of colonic preneoplastic lesions, aberrant crypt foci, was not significantly different in the QUE-fed azoxymethane-treated rats when compared to azoxymethane-treated vehicle-fed rats at the conclusion of 7 week feeding period. We found no correlation between immune function and development of preneoplastic colon lesions in this study.

Animals↗