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PubMed1998

Slow-release pellets of sodium butyrate increase apoptosis in the colon of rats treated with azoxymethane, without affecting aberrant crypt foci and colonic proliferation.

We investigated whether sodium butyrate, administered orally as gastroresistant slow-release pellets to rats, could affect markers of colon carcinogenesis. F344 male rats were fed a high-fat diet (230 g/kg corn oil, wt/wt) and treated with two injections (1 wk apart) of azoxymethane (15 mg/kg sc) or saline. Rats were then divided into two groups: one received the diet with 1.5% (wt/wt) sodium butyrate for 10 weeks to provide 150 mg butyrate/day, and one group received no butyrate. At the end of this period, rats were sacrificed, and colonic proliferative activity, number of aberrant crypt foci (ACF), and apoptosis were assessed in the colon. The proliferative activity and ACF induction were not affected by butyrate pellet administration. On the contrary, in rats treated with butyrate, apoptotic index increased from 0.12 +/- 0.12 to 0.81 +/- 0.10 (means +/- SE, p < 0.05). The short-chain fatty acid concentration was significantly increased in the feces of rats treated with butyrate. In conclusion, the increase in the mucosal apoptotic index suggests that gastroresistant butyrate pellets have a beneficial effect against colon carcinogenesis. However, because butyrate pellets did not modify proliferation or ACF induction, this conclusion should be confirmed in long-term carcinogenesis experiments.

Animals↗
PubMed1989

Inositol hexaphosphate inhibits large intestinal cancer in F344 rats 5 months after induction by azoxymethane.

A treatment regimen of 2% Na-InsP6 in drinking water was effective in significantly reducing large intestinal cancer in F344 rats even when the treatment was begun 5 months after carcinogenic induction with azoxymethane (AOM 8 mg/kg/wk X 6). Compared to untreated (AOM-only) rats, animals on InsP6 had 27% fewer tumors (P less than 0.02). The tumors were approximately two-thirds smaller in size (P less than 0.01) and percentage mitotic rate in the non-neoplastic epithelium was less than half (1.0 +/- 0.1, compared to 2.3 +/- 0.2 of AOM-only animals, significant at P less than 0.001). We postulate that InsP6 may exert its antineoplastic effect by way of regulating cellular proliferation even after effective carcinogenic stimuli and thus may be an important candidate for chemointervention.

Animals↗
PubMed1991

Metabolism of azoxymethane, methylazoxymethanol and N-nitrosodimethylamine by cytochrome P450IIE1.

The metabolism of azoxymethane (AOM), methylazoxymethanol (MAM) and N-nitrosodimethylamine (NDMA) by liver microsomes from acetone-induced rats as well as by a reconstituted system containing purified cytochrome P450IIE1 was examined. The products consisted of MAM from AOM; methanol and formic acid from MAM; and methylamine, formaldehyde, methanol, methylphosphate and formic acid from NDMA. Compared to liver microsomes from untreated rats, the metabolic activity of acetone-induced microsomes was approximately 4 times higher for all three carcinogens. Using the reconstituted system, the enzyme activities (nmol substrate metabolized/nmol P450/min) for AOM, MAM and NDMA were 2.88 +/- 1.14, 2.87 +/- 0.59 and 9.47 +/- 2.24 respectively. Incubations carried out in the presence of a monoclonal antibody to cytochrome P450IIE1 resulted in a 85-90% inhibition of all three reactions in this system. These results provide conclusive evidence that AOM, MAM and NDMA are metabolized by the same form of rat liver cytochrome P450. In addition, the stoichiometry of NDMA products formed in these reactions indicates that denitrosation, a presumed detoxication process, and alpha-hydroxylation, an activation reaction, are also catalyzed by the same cytochrome P450 isozyme.

Acetone↗
PubMed1991

Inhibition of azoxymethane-induced neoplasia of the large bowel by 3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene (nerolidol).

The inhibitory capacities of four terpenes on azoxymethane (AOM)-induced neoplasia of the large bowel and duodenum was studied in male F344 rats. A complete course of AOM administrations was given and 3 days later the rats were fed a semipurified diet containing 5 mg/g of the test compounds, i.e. 3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene (nerolidol), beta-citronellol, (+/-)-linalool and (1R,2S,5R)-(-)-menthol or a corresponding control diet. The experiment was terminated 22 weeks after the last dose of AOM. Under these conditions, nerolidol showed an inhibitory effect on carcinogenesis of the large bowel. The number of rats bearing large bowel neoplasms (adenomas) was reduced from 82% in the controls to 33% in rats fed nerolidol and the number of tumors/rat from 1.5 in the controls to 0.7 in the nerolidol group. A reduction in adenocarcinomas of the duodenum was found but the data are not statistically significant. The effects of nerolidol are of interest in terms of the identification of a new inhibitor of carcinogenesis of the large bowel. The chemical structure of nerolidol suggests the possibility that the compound might have an impact on protein prenylation or some other aspect of the mevalonate pathway, but this remains to be established.

Animals↗
PubMed1991

Effects of gastrointestinal peptides on azoxymethane-treated colonic mucosa in vitro.

An organ-culture system has been used to investigate the effect of certain gastrointestinal peptides on the morphology and cell proliferation of explants of azoxymethane (AOM)-treated colonic mucosa. Our aim was to ascertain whether such factors play a direct part in the maintenance of hyperplastic changes in the large intestine. Explants of AOM-treated colonic mucosa from 15 animals were maintained in a serum-free medium in the presence of either gastrin-17 (250 pg/ml and 250 ng/ml), peptide YY (80 pmol/l and 160 pmol/l) epidermal growth factor (EGF) (10 ng/ml and 100 ng/ml) or the C-terminal fragment of glucagon-37 (30 pmol/l) for a period of up to 7 days. Other explants (controls) received fresh medium only each day. After 1, 2, 3, 5 and 7 days of culture both experimental and control explants received vincristine (4 micrograms/ml) for 3 h prior to fixation. The proportion of vincristine-arrested metaphases within the explants was determined together with crypt length. Neither gastrin nor peptide YY was found to influence cell division at either concentration. Despite an initial inhibitory effect, both concentrations of EGF exerted a trophic effect which increased with time. The glucagon-37 fragment caused an immediate increase in proliferation which then declined as time progressed. None of these factors, however, were able to maintain the hyperplastic changes seen in the pre-culture samples of AOM-treated mucosae.

Animals↗
PubMed1991

Inhibition by dietary oltipraz of experimental intestinal carcinogenesis induced by azoxymethane in male F344 rats.

Epidemiological studies suggest that consumption of cruciferous vegetables rich in dithiolethiones is associated with a reduction in the incidence of cancer in man. The effect of two dose levels of dietary oltipraz [5-(2-pyrazinyl)-4-methyl-1, 2- dithiole-3-thione], a substituted dithiolethione, on azoxymethane (AOM)-induced intestinal carcinogenesis and on serum levels was studied in male F344 rats. The maximum tolerated dose (MTD) of oltipraz was determined in male F344 rats and found to be 500 p.p.m. Oltipraz at levels of 200 p.p.m. (40% MTD) and 400 p.p.m. (80% MTD) diet was tested as inhibitor of intestinal carcinogenesis. At 5 weeks of age, animals were fed the modified AIN-76A (control) diet and experimental diets containing oltipraz. At 7 weeks of age, all animals except the vehicle-treated animals were administered s.c. injection of AOM (15 mg/kg body wt/week for 2 weeks). Animals intended for vehicle treatment were administered s.c. with an equal volume of normal saline. Fifty-two weeks later, all animals were killed and colon and small intestinal tumor incidences and multiplicity were compared among the dietary groups. The results indicate that feeding of 200 and 400 p.p.m. of oltipraz significantly inhibited the incidence of adenocarcinomas in colon and small intestine and multiplicity of colon adenomas and small intestinal adenocarcinomas. Animals fed 400 p.p.m. oltipraz showed increased levels of oltipraz in the serum as compared to those fed 200 p.p.m. oltipraz. The results of this study indicate that dietary oltipraz inhibits intestinal carcinogenesis.

Animals↗
PubMed1991

Effect of disulfiram on 1,2-dimethylhydrazine- and azoxymethane-induced aberrant crypt foci.

We have previously reported a method for visualizing the mucosal surface of fixed unsectioned rodent colons at the crypt level and have identified lesions, termed aberrant crypt foci (ACF), in the colons of carcinogen-treated rodents. We hypothesized that ACF represent the precursor lesions (PL) of colon cancer. In the present study, the effect of feeding disulfiram (DSF) added to a semi-synthetic diet (0.5% or 1% by wt) on 1,2-dimethylhydrazine (DMH) and azoxymethane (AOM) induced ACF was investigated. DSF has been shown to inhibit DMH and AOM-induced colon cancer. Therefore, it was reasoned that if ACF represent PL then their induction and growth should also be inhibited by DSF. CF1 female mice were randomly divided into three groups of 30 each. Group 1 was fed a diet containing 1% DSF for 9 days prior to and 1 day after receiving a single i.p. injection of either DMH, AOM or saline. Group 2 was fed a diet containing 1% DSF for 9 days prior to and 14 days after receiving a single i.p. injection of DMH, AOM or saline, whereas group 3 received control diet throughout the experimental duration. All animals were killed 5 weeks after receiving the injections. It was observed that feeding DSF, for 9 days prior to and for either 1 day or 14 days after the administration of a single injection of DMH, resulted in a complete inhibition of ACF. DSF feeding for 9 days prior to and 1 day after AOM injection resulted in a significantly greater number of ACF compared to the control group (12 +/- 2.3 vs 7.2 +/- 1.2); whereas DSF feeding for a longer duration (i.e. 9 days prior to and 14 days after AOM treatment) was associated with a significantly lower number of ACF compared to those fed DSF for only one day after AOM treatment (4.1 +/- 0.6 vs 12.4 +/- 2.3) and a lower number compared to the control group (4.1 +/- 0.6 vs 7.2 +/- 1.2).

1,2-Dimethylhydrazine↗
PubMed1992

Evidence for a ras gene mutation in azoxymethane-induced colonic aberrant crypts in Sprague-Dawley rats: earliest recognizable precursor lesions of experimental colon cancer.

The main objective of the present investigation was to understand the molecular events involved in the genesis of aberrant crypt foci. Aberrant crypt foci were induced in Sprague-Dawley rats with a single injection of azoxymethane. Aberrant crypts have been identified topographically in the colon and are hypothesized to represent preneoplastic lesions. In order to understand the molecular events involved in the early stages of colon cancer, PCR-amplified DNA from aberrant crypts was hybridized with oligonucleotide probes specific for the detection of point mutations in codon 12 of K-ras. The mutation identified was a G to A transition resulting in the substitution of the amino acid aspartic acid (asp) for glycine (gly). This mutation was present in 6/19 (32%) of aberrant crypts examined. The identical mutation was also identified in adenomacarcinoma tissue while no mutation could be detected in normal intestinal mucosa. For further confirmation of these results, the presence of the mutated ras protein (rasAsp-12) was detected in aberrant crypts by immunohistochemistry. This investigation provides the first identification of a ras point mutation in aberrant crypt foci.

Adenocarcinoma↗
PubMed1992

Aberrant crypts correlate with tumor incidence in F344 rats treated with azoxymethane and phytate.

Aberrant crypts are putative preneoplastic lesions that have been proposed as intermediate biomarkers for colon cancer. The goals of these studies were to determine (i) if the colon cancer chemopreventive agent, sodium phytate, when started 1 week after a single dose of carcinogen, has any effect on the development of aberrant crypt foci (ACF) in treated rats; and (ii) if ACF at an early time period under these conditions correlate with the later formation of tumors in similarly treated animals. The number of ACF with four or more crypts was greater (P = 0.02, Mann-Whitney test) in rats with tumors compared with rats without tumors killed at 36 weeks after the injection of azoxymethane (AOM); the total number of ACF was not significantly different in these two groups. The incidence of tumors in F344 rats treated with AOM without phytate was 83% (10/12) compared to 25% (3/12) in rats treated with AOM plus phytate (P = 0.0045, two-tail Fisher's exact test). The finding of more (P = 0.005, Mann-Whitney test) ACF with four or more crypts in rats without phytate than in rats with phytate at 12 weeks after the injection of AOM is consistent with the hypothesis that the development of larger ACF (with four or more crypts) is predictive of the tumor incidence. These results validate the use of this parameter, i.e. ACF with four or more crypts, as an intermediate biomarker for tumor incidence in this system.

Animals↗
PubMed1993

Inhibition by dietary curcumin of azoxymethane-induced ornithine decarboxylase, tyrosine protein kinase, arachidonic acid metabolism and aberrant crypt foci formation in the rat colon.

The present study was designed to investigate the modulatory role of dietary curcumin on (i) azoxymethane (AOM)-induced ornithine decarboxylase (ODC), tyrosine protein kinase (TPK) and arachidonic acid metabolism in liver and colonic mucosa of male F344 rats, (ii) in vitro arachidonic acid metabolism in the liver and colonic mucosa and (iii) AOM-induced aberrant crypt foci (ACF) formation in the colon of F344 rats. At 5 weeks of age groups of animals were fed one of the experimental diets containing 0 or 2000 p.p.m. curcumin. Two weeks later all the animals except the vehicle-treated groups were given s.c. injections of AOM, 15 mg/kg body wt, once weekly for 2 weeks. The animals intended for biochemical study were killed 5 days later and the colonic mucosa and liver were analyzed for ODC, TPK, lipoxygenase and cyclo-oxygenase metabolites. The animals intended for ACF study were killed 9 weeks later and analyzed for ACF in the colon. The results indicated that in saline-treated animals dietary curcumin significantly inhibited the ODC (P < 0.001) and TPK (P < 0.05) activities in the liver and colonic mucosa. Dietary curcumin significantly decreased the levels of AOM-induced ODC activity in the liver and colon (P < 0.0001) and TPK activity in the liver and colon (P < 0.01-0.0001) and the formation of 5(S)-, 8(S)-, 12(S)- and 15(S)-hydroxyeicosatetraenoic acids (HETEs) in the liver and colon (P < 0.0001). Also, curcumin suppressed AOM-induced prostaglandin (PG) and thromboxane (Tx) formation in the liver (PGE2, PGF2 alpha, PGD2, 6-keto-PGF1 alpha and TxB2 to 40, 59, 55, 53 and 39% respectively) and in the colon (PGE2 and PGF2 alpha to 39 and 41% respectively). Further, dietary curcumin reduced the in vitro formation of HETEs, PGs and Tx in a dose-dependent manner. AOM-induced colonic ACF were significantly (P < 0.001) inhibited in the animals fed the curcumin diet. The results of the present study indicate that curcumin, present in turmeric, inhibits AOM-induced colonic preneoplastic lesions and other cellular events relevant to colon carcinogenesis.

Animals↗
PubMed1993

Intermediate biomarkers of colon cancer: modulation of expression of ras oncogene by chemopreventive agents during azoxymethane induced colon carcinogenesis.

In our attempts to evaluate the influence of chemopreventive agents on intermediate biomarkers of colon cancer, we have investigated the effect of D,L-alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase and piroxicam, a non-steroidal anti-inflammatory drug (NSAID) on the expression levels of biochemically active p21ras, the protein product of cellular ras protooncogenes during the development of azoxymethane (AOM) induced colon carcinogenesis in male F344 rats in order to explore the plausibility of using p21ras as an intermediate biochemical marker of colon cancer. Groups of male F344 rats were fed the modified AIN-76A diets containing 0 or 150 p.p.m. piroxicam or 4000 p.p.m. DFMO and administered s.c. AOM dissolved in normal saline at a dose of 15 mg/kg body wt/week, once weekly, for 4 weeks. Vehicle control groups received s.c. equal vol of normal saline. Groups of animals were then killed at 0, 4, 16, 24 and 32 weeks after the last injection of AOM or saline and their colonic mucosa and tumors analyzed for biochemically active p21ras levels. AOM treatment significantly increased the expression of biochemically active p21ras. The AOM-induced expression of biochemically active p21ras was significantly suppressed by dietary DFMO and piroxicam. DFMO exerted a more pronounced inhibitory effect on AOM-induced colon tumor development as well as the expression of biochemically active p21ras. These results indicate that the determination of biochemically active p21ras may be effectively used in clinical chemoprevention trials as an intermediate end-point to monitor the colon carcinogenesis.

Affinity Labels↗
PubMed1993

Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats.

Epidemiologic studies suggest that sustained use of aspirin may reduce the risk of development of and mortality due to colon cancer. Previous preclinical studies have shown that several non-steroidal anti-inflammatory drugs act as potential chemopreventive agents in experimentally induced colon cancer models. The present study was designed to investigate the chemopreventive effect of 40 and 80% maximum tolerated dose (MTD) levels of aspirin administered in the diet on azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. The MTD of aspirin as determined in male F344 rats was 500 p.p.m. Beginning at 5 weeks of age, all animals were randomly divided into various experimental groups (48 rats/group) and fed one of the semipurified diets containing 0, 200 p.p.m. (40% MTD), or 400 ppm (80% MTD) of aspirin. Two weeks later, all animals (36 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM at a dose level of 15 mg/kg body wt, once weekly for 2 weeks. All animals were continued on their respective dietary regimen for additional 52 weeks and necropsied. Histopathologic evaluation of colon tumors was performed by routine procedures. Basal levels and ex vivo production of colonic mucosal and tumor prostaglandin E2 (PGE2) were measured in all groups. The results indicate that daily oral administration of 200 and 400 p.p.m. aspirin significantly inhibited the incidence (% animals with tumors) and multiplicity (tumors/animal) of invasive adenocarcinomas of the colon as well as the size of adenocarcinomas. Colonic mucosal and tumor PGE2 levels (basal and ex vivo production) were significantly reduced in animals administered 200 and 400 p.p.m. aspirin. The results of this study support the epidemiologic evidence that ingestion of aspirin inhibits colon carcinogenesis. Although the precise mechanisms of aspirin-induced colon tumor inhibition remain to be determined, it is likely that the effect may be mediated through the modulation of prostaglandin synthesis.

Adenocarcinoma↗
PubMed1993

Enhancement by the tricyclic antidepressant, desipramine, of experimental carcinogenesis in rat colon induced by azoxymethane.

The effects of the tricyclic antidepressant drug desipramine on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the serum norepinephrine (NE) concentration and the labeling index of colon mucosa were investigated in Wistar rats. Rats were treated s.c. with 7.4 mg AOM/kg body wt once a week for 10 weeks, and also s.c. with 10 mg desipramine hydrochloride (desipramine)/kg body weight until the end of the experiment. Treatment with desipramine significantly increased the incidence, but not the number, of colon tumors in week 35. However, it did not influence the location and the histological appearance of the colon tumors or the histological types of colon adenocarcinomas. Furthermore, it significantly increased the serum NE level and the labeling index of colon mucosa during and after AOM treatment. These findings indicate that desipramine enhanced the development of colon tumors and that its effect may be related to its effect in increasing proliferation of colon epithelial cells.

Animals↗
PubMed1994

Sequential analysis of K-ras mutations in aberrant crypt foci and colonic tumors induced by azoxymethane in Fischer-344 rats on high-risk diet.

Forty Fischer-344 male rats were given a high-risk diet (HRD) that was high in fat, low in fiber and low in calcium. After 4 weeks, the rats were given two weekly s.c. injections of azoxymethane (AOM, 15 mg/kg body wt), and remained on the same diet till death. Eight rats were killed at 12 weeks and again at 20 weeks in order to microdissect aberrant crypt foci (ACF) containing four or more crypts/focus from their colons. The remaining 24 rats were killed at 30 weeks to harvest colonic tumors. The polymerase chain reaction (PCR) was used to amplify specific DNA segments in the K-ras gene from ACF and colonic tumors. The PCR-amplified DNAs were sequenced to identify the point mutations in codons 12 and 13. All the mutations detected in the ACF and colonic tumors were G to A transitions in the second position of codon 12. These mutations were present in the ACF of 2/8 (25%) and 3/8 (37%) rats at 12 and 20 weeks respectively. The mutations were present in colonic tumors of 7/24 (29%) rats. These results provide important evidence for the significance of K-ras mutations in ACF (> 4 crypts/focus) as early markers of malignant potential in the colons of F344 rats exposed to AOM while receiving a high-risk western style diet.

Adenocarcinoma↗
PubMed1994

Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents.

Foci of aberrant and/or hexosaminidase-negative crypts in rat colon are putative precancerous lesions that have been proposed as biomarkers for short-term bioassays for chemical carcinogens and chemopreventive agents. The ability of a substance to reduce the yield of azoxymethane (AOM)-induced foci in the colon of male Fischer 344 rats, was evaluated as a screening assay for chemopreventive agents. Twenty-eight test agents were administered continuously in the diet from the start of the experiments until the animals were killed 35 days later. AOM was s.c. administered either as 15 mg/kg body wt on days 7 and 14 or as 30 mg/kg body wt on day 7 of the experiment. Foci of aberrant crypts were evaluated in whole mounts of methylene blue-stained colons. AOM induced twice as many foci when administered between 8.40 and 11.00 a.m. than between 2.45 and 5.55 p.m. Calcium salts of carbonate, chloride and glucarate decreased the yield of AOM-induced foci while the acidic salts of lactate and phosphate did not inhibit the formation of foci. Dimethyl-fumarate, fumaric acid, genistein, piroxicam, simethicone, sodium suramin and sulindac reduced the yield of AOM-induced foci of aberrant crypts, with genistein being the most potent. Only piroxicam of this group has previously been shown to inhibit colon cancer, while the rest have yet to be evaluated. Ibuprofen did not inhibit the formation of foci, although it has been reported to inhibit AOM-induced colon cancer in rats. Piroxicam and sulindac appeared to reduce preferentially hexosaminidase-negative foci of aberrant crypts, compared with those of apparently normal morphology. The AOM-induced foci of aberrant crypts assay appears suitable for screening chemicals for chemopreventive action.

Animals↗
PubMed1994

Modulation of azoxymethane-induced mutational activation of ras protooncogenes by chemopreventive agents in colon carcinogenesis.

In our previous study, we demonstrated that azoxymethane (AOM) treatment significantly enhanced the expression of ras p21, the protein product of ras genes, and that the dietary administration of chemopreventive agents such as D,L-alpha-difluoromethylornithine (DFMO), a irreversible inhibitor of ornithine decarboxylase, and piroxicam, a non-steroidal anti-inflammatory drug (NSAID), exerted a significant inhibitory effect on AOM-induced ras p21 expression. In the present study, which is an extension of our earlier investigation, we have determined the effect of DFMO and piroxicam on mutational activation of ras protooncogenes during AOM-induced colon carcinogenesis. Groups of male F344 rats were fed the modified AIN-76A diet containing 0 or 150 p.p.m. piroxicam, or 4000 p.p.m. DFMO and administered s.c. AOM dissolved in normal saline at a dose rate of 15 mg/kg body wt, once weekly, for 4 weeks. Vehicle control groups received s.c. equal volumes of normal saline. Groups of animals were then killed at 0, 4, 16, 24 or 32 weeks after last AOM or saline injection. AOM-induced colon tumors and colonic mucosa from AOM treated as well as saline treated animals were analyzed for point mutations in K- and H-ras protooncogenes by a combination of polymerase chain reaction mediated restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. Our results demonstrate that of the total 65 AOM-induced colon tumors analyzed, 45/50 (90%) obtained from AOM-treated animals fed the control diet, 4/11 (36%) from AOM-treated animals fed piroxicam diet, and 1/4 (25%) from AOM-treated animals fed the DFMO diet, contained single-point mutations occurring specifically at the second nucleotide of codon 12 which were identified exclusively as G to A transitions in case of K-ras, and G to A transitions and also G to T transversions in H-ras. Similar point mutations were identified in colonic mucosa of 21/30 (70%) of AOM-treated animals fed the control diet, 10/30 (33%) of AOM-treated animals fed piroxicam diet, and none of 30 (0%) of AOM-treated animals fed DFMO diet. These results indicate that the administration of piroxicam and DFMO may inhibit the selective amplification of AOM-induced initiated cells carrying mutated ras genes. Dietary DFMO exerted more pronounced inhibition of selective amplification of initiated cells containing AOM-induced mutant ras. Data suggest that determination of ras activation may be a useful marker for chemoprevention of colon cancer.

Animals↗
PubMed1995

Effect of beta-carotene and wheat bran fiber on colonic aberrant crypt and tumor formation in rats exposed to azoxymethane and high dietary fat.

The typical high-fat, low-fiber American diet promotes colon cancer. An alternative to radical changes in dietary habits is to reinforce the diet with cancer protectors. Experiments to evaluate the effects of beta-carotene in the presence of high fat and low and high dietary levels of wheat bran fiber were designed using the Fischer-344 rat colon cancer model. Rats (20/group), were given either high fat (20% w/w), low wheat bran, fiber (1% w/w) diets, or high fat (20% w/w) high wheat bran fiber (8% w/w) diets, with different levels of beta-carotene. After 2 weeks of adaptation, half were given two weekly s.c. injections of azoxymethane (AOM, 15 mg/kg body wt); and half two weekly s.c. injections of saline. Six weeks later, five rats from each dietary group were killed to evaluate the comparative effect of different dietary regimens on the induction of colon aberrant crypt foci (ACF). The remaining rats were maintained on their respective diets for an additional 20 weeks to examine the effect on colon tumor incidence. The total number of ACF/rat in the low-fiber groups declined from 44.0 +/- 4.18 to 12.8 +/- 1.95 in response to increasing amounts of beta-carotene from 1 to 20 mg/kg diet. A similar progressive reduction in total ACF/rat was also seen in the high-fiber groups (20.8 +/- 2.92 to 9.2 +/- 0.58). ACF did not develop in the saline-exposed groups. Similarly colon tumor incidence declined from 73% to 20% in high-fiber groups and from 27% to 13% in low-fiber groups in response to increasing amounts beta-carotene from 1 to 20 mg/kg diet. The results showed that beta-carotene and wheat bran, individually and when combined, protected the colon in rats consuming high-fat, western-style diets from ACF and benign or malignant tumor formation.

Animals↗
PubMed1995

Suppression of azoxymethane-induced rat colon carcinogenesis by dietary administration of naturally occurring xanthophylls astaxanthin and canthaxanthin during the postinitiation phase.

The modulating effects of dietary feeding of two xanthophylls, astaxanthin (AX) and canthaxanthin (CX) during the postinitiation phase on colon carcinogenesis initiated with azoxymethane (AOM) were investigated in male F344 rats. Animals were initiated with AOM by weekly s.c. injections of 15 mg/kg body wt for 3 weeks and then they were fed the diets containing AX or CX at concentrations of 100 and 500 p.p.m. for 34 weeks. The others contained the groups of rats treated with AX or CX alone and untreated. At the end of the study (week 37), the incidence and multiplicity of neoplasms (adenoma and adenocarcinoma) in the large intestine of rats initiated with AOM and followed by AX or CX containing diet at a high dose (500 p.p.m.) were significantly smaller than those of rats given AOM alone (P < 0.001). In addition, AX or CX feeding significantly inhibited the development of aberrant crypt foci induced by AOM. Dietary exposure to AX or CX also decreased cell proliferation activity as revealed by measuring 5'-bromodeoxyuridine-labeling index as crypt cells, colonic mucosal ornithine decarboxylase activity and blood polyamine levels. These results indicate that AX and CX are possible chemopreventers for carcinogenesis of colon in addition to urinary bladder and oral cavity and such effects may be partly due to suppression of cell proliferation.

Animals↗