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PubMed1998

Suppressive effects of nimesulide, a selective inhibitor of cyclooxygenase-2, on azoxymethane-induced colon carcinogenesis in mice.

The effects of nimesulide, a selective inhibitor of cyclooxygenase-2 (COX-2) on azoxymethane (AOM)-induced colon carcinogenesis were investigated in mice. AOM at a dose of 10 mg/kg body wt was administered to male ICR mice once a week for 6 weeks. The animals were fed on AIN-76A powder diet containing nimesulide at doses of 200 or 400 p.p.m., starting the day before the first carcinogen treatment until the end of the experiment, at week 30. Administration of nimesulide reduced the incidence of colon carcinomas to 32 and 25% for the AOM + 200 and 400 p.p.m. nimesulide groups, respectively, compared with the AOM + basal diet group (50%). Multiplicities of colon carcinomas in the 200 and 400 p.p.m. nimesulide-treated groups were 0.70 +/- 0.28 and 0.35 +/- 0.11, respectively, being significantly smaller than the AOM alone value (1.79 +/- 0.47). The sizes of the colon carcinomas in the nimesulide-treated groups were also decreased. No significant influence on liver and lung tumor development was apparent. Thus, nimesulide exerted a suppressive effect on AOM-induced colon carcinogenesis in mice.

Animals↗
PubMed1998

Altered expression of cyclin D1 and cyclin-dependent kinase 4 in azoxymethane-induced mouse colon tumorigenesis.

Alterations in the expression of the cell cycle regulators, cyclin D1 and cyclin-dependent kinase 4 (Cdk4), have been implicated in malignancies of both humans and experimental animal models. We hypothesize that altered expression of cyclin D1 and Cdk4 may also be involved in mouse colon tumorigenesis induced by the chemical carcinogen, azoxymethane (AOM). In the present study, SWR/J mice were given AOM by i.p. injection at a dose of 10 mg/kg once a week for 8 weeks, and colonic tissue and tumors were isolated 18 weeks later. The expression and localization of cyclin D1 and Cdk4 were examined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analyses. Cyclin D1 and Cdk4 mRNA levels in tumor samples were increased 1.3-fold (P < 0.01) and 1.2-fold (P < 0.01), respectively, when compared with control mouse colon tissue. Control colon epithelium was uniformly negative for cyclin D1 immunoreactivity, whereas minimal Cdk4 nuclear staining was confined to the lower portion of the crypts within the control tissue. Both cyclin D1 and Cdk4 immunoreactive cells were markedly increased in preneoplastic lesions and in adenomas isolated from AOM-treated mice. Furthermore, some morphologically normal colon crypts from AOM-treated mice showed positive cyclin D1 immunoreactivity. These findings suggest that overexpression of cyclin D1 and Cdk4 occurs early in the AOM-induced mouse colon tumorigenesis and may contribute to tumor progression in this model.

Animals↗
PubMed1999

Dietary prevention of azoxymethane-induced colon carcinogenesis with rice-germ in F344 rats.

The modifying effect of dietary administration of defatted rice-germ and gamma-aminobutyric acid (GABA)-enriched defatted rice-germ on azoxymethane (AOM)-induced colon carcinogenesis was investigated in two experiments with male F344 rats. In the first experiment (the pilot study), the effects of the defatted rice-germ, the GABA-enriched defatted rice-germ and rice-germ on AOM-induced (15 mg/kg body wt once a week for 3 weeks) formation of aberrant crypt foci (ACF) were examined. The latter two preparations (2.5% in the diet) significantly inhibited ACF formation (P < 0.005). In the second experiment, a long-term study of the effects of rice-germ was done. One group was treated with AOM alone, four groups received the carcinogen and were fed the diets containing 2.5% rice-germ or 2.5% GABA-enriched defatted rice-germ for 5 (initiation phase) or 30 weeks (post-initiation phase), two groups were treated with rice-germ or GABA-enriched defatted rice-germ alone and one group was kept on the basal diet. At the termination of the study, dietary exposure to rice-germ during the initiation phase significantly reduced the incidence of colonic adenocarcinoma (71 versus 29%, P < 0.01). GABA-enriched defatted rice-germ or rice-germ during the post-initiation phase also decreased the frequency of colonic adenocarcinoma (71 versus 20%, GABA-enriched defatted rice-germ feeding, P < 0.01; 27%, rice-germ feeding, P < 0.01). These data suggest that constituents of rice-germ are possible dietary preventatives for human colon cancers.

Animals↗
PubMed1999

Inhibition of O(6)-methylguanine-DNA methyltransferase increases azoxymethane-induced colonic tumors in rats.

Azoxymethane (AOM) causes O(6)-methylguanine adduct formation which leads to G-->A transitions. Their repair is carried out by O(6)-methylguanine-DNA methyltransferase (MGMT). To evaluate the importance of this repair event in AOM-induced carcinogenesis, we examined the effect of O(6)-benzylguanine (BG), a potent inhibitor of MGMT, on colonic tumor development. Rats were treated weekly for 2 weeks at 0 and 24 h with BG (60 mg/kg body wt i.p.) or vehicle (40% polyethylene glycol, PEG-400), followed 2 h after the first dose of BG with AOM (15 mg/kg body wt) or vehicle (saline) i.p. Rats were killed 35 weeks later and tumors harvested and DNA extracted. In the AOM-treated groups, BG caused a significant increase in tumor incidence with tumors in 65.9%, versus 30.8% in the AOM/PEG-treated group (P < 0.05). In the BG/AOM group there was also a significant increase in tumor multiplicity, with 2.3 tumors/tumor-bearing rat, versus 1.6 tumors/tumor- bearing rat in the AOM/PEG group (P < 0.05). Since O(6)-methylguanine adducts can cause activating mutations in the K-ras and beta-catenin genes, we examined the effects of BG on these mutations. In the BG group there were seven mutations in codon 12 or 13 of exon 1 of the K-ras gene in 51 tumors examined, compared with no K-ras mutations in 17 tumors analyzed in the AOM/PEG group (P = 0.12). In the BG/AOM group there were 10 mutations in exon 3 of the beta-catenin gene among 48 tumors evaluated, compared with six mutations in 16 tumors analyzed in the PEG/AOM group (P = 0.16). In summary, MGMT inhibition increases AOM-induced colonic tumor incidence and multiplicity in rats.

Animals↗
PubMed1999

Coordinate regulation of cyclooxygenase-2 and TGF-beta1 in replication error-positive colon cancer and azoxymethane-induced rat colonic tumors.

Evidence is accumulating which indicates that cyclooxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)-induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-beta1 staining pattern in these human and rat tumors was similar to that observed for COX-2. The role of TGF-beta in RER adenocarcinomas is complex because of the increased mutation rate of TGF-beta type II receptors. Northern analysis showed abundant TGF-beta1 mRNA in AOM-induced tumors, but not in paired mucosa. TGF-beta1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6). Chronic TGF-beta1 treatment caused a TGF-beta-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1). TGF-beta1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence.

Animals↗
PubMed1999

Prevention by aspirin and its combination with alpha-difluoromethylornithine of azoxymethane-induced tumors, aberrant crypt foci and prostaglandin E2 levels in rat colon.

The dose-response relationship in male F344 rats was determined for the ability of aspirin administered in the diet to prevent azoxymethane (AOM)-induced colon cancer and aberrant crypt foci (ACF) and to reduce prostaglandin E2 (PGE2) levels. Starting at either 7 or 22 weeks of age, the rats received aspirin. All rats received two doses of AOM (15 mg/kg each on days 7 and 14) and were killed on day 36. The lowest concentrations of aspirin to prevent ACF or reduce PGE2 levels were 600 and 400 mg/kg, respectively. To evaluate the prevention of tumors, rats received either 0 or 400 mg/kg aspirin for a total of 39 weeks with AOM (30 mg/kg) administered 7 days after the start of treatment. Aspirin had no effect on the yield of colon tumors. In a second experiment, rats started to receive 0, 200, 600 or 1800 mg/kg aspirin or 1000 mg/kg alpha-difluoromethylornithine (DFMO) +/- aspirin. Eight and 15 days later, all the rats received 15 mg/kg AOM. Eleven weeks later, animals that were receiving the control diet started to receive 0, 200, 600 or 1800 mg/kg aspirin; 1000 or 3000 mg/kg DFMO; or 1000 mg/kg DFMO + 200 or 600 mg/kg aspirin. The animals were killed 32 weeks later. DFMO effectively reduced the yield of colon tumors when administered starting either before or after AOM while aspirin was much weaker. The combination of aspirin + DFMO administered after AOM was synergistic. Both aspirin and DFMO decreased the Mitotic Index, while apoptosis was increased only by DFMO. Our results demonstrated that aspirin and DFMO could prevent colon cancer when administered after AOM. Furthermore, aspirin reduced ACF, PGE2 levels and mitosis at concentrations that did not prevent cancer. In contrast, the ability to enhance apoptosis did correlate with the prevention of cancer.

Animals↗
PubMed1999

Preliminary analysis of azoxymethane-induced colon tumorigenesis in mouse aggregation chimeras.

Inbred mice exhibit differential susceptibility to colon carcinogens. The following study addresses the possibility that differences are intrinsic to colonic mucosa (cell autonomous) or are mediated by extracolonic systemic factors (e.g. liver activation of carcinogens). Our approach was to construct mouse aggregation chimeras, mice whose tissues are a mosaic of cells derived from two parental genotypes, from a susceptible (SWR) and a resistant (DBA/2) strain. Forty-five embryo aggregations yielded 11 viable pups, four of which were chimeric by coat color. Six-week-old SWR<-->BA/2 chimeras were injected i.p. with azoxymethane (AOM) once a week for 8 weeks (5 and 7.5 mg/kg body wt for 2 weeks followed by 10 mg/kg for 6 weeks) and tumor incidence in distal colon was evaluated 15 weeks after the last injection. Additional groups of parental mice received the same treatment. In the parental SWR treatment group, 1.7 +/- 0.82 tumors/colon were found. No tumors were observed in AOM-treated DBA/2 mice. In SWR<-->DBA/2 chimeras exposed to AOM, 2.8 +/- 2.1 tumors/colon were found. Tumor lineage was examined in paraffin sections stained with Dolichos biflorus agglutinin-peroxidase, a cell surface specific marker that stains intestinal endothelial cells of SWR and epithelial cells of DBA/2. Cellular lineage of tumors was further evaluated by microsatellite analysis of DNA isolated by microdissection. There was no significant difference in tumor incidence between SWR parental and chimera treatment groups. Histochemical analysis of tumor tissue in chimeras suggested that most tumors were derived from SWR. However, subsequent genetic analysis of tumors indicated mixed parental composition. These preliminary studies suggest that DBA/2 resistance mechanisms are not sufficient to protect adjacent SWR-derived epithelium from the tumorigenic effects of AOM.

Animals↗
PubMed1999

Polyethylene-glycol, a potent suppressor of azoxymethane-induced colonic aberrant crypt foci in rats.

Bulking fibers and high water intake may decrease colon carcinogenesis in rats, and the risk of colorectal cancer in humans. We speculated that a non-fermented polymer, polyethylene-glycol (PEG) 8000, which increases stool moisture, might protect rats against colon carcinogenesis. Thirty female F344 rats were given a single injection of azoxymethane (20 mg/kg), and 7 days later randomized to AIN76 diets containing PEG (to provide 3 g/kg body wt/day), or no PEG (control). Diets were given ad libitum for 105 days, then colon carcinogenesis was assessed by the aberrant crypt foci (ACF) test. ACF were scored blindly by a single observer. Dietary feeding of PEG almost suppressed ACF larger than one crypt, and strikingly decreased the total number of ACF per rat. PEG-fed rats had 100 times less large ACF than controls (0.8 and 83 respectively, P = 0.00001). PEG-fed rats had 20 times less total ACF than control (six and 107 ACF/rat, respectively; P < 0.0001). Two treated rats had no detectable ACF. PEG is 10 times more potent than other chemopreventive agents in this model. Since PEG is generally recognized as safe, its cancer-preventive features could be tested in humans.

Animals↗
PubMed1999

Effects of soy or rye supplementation of high-fat diets on colon tumour development in azoxymethane-treated rats.

Evidence is accumulating that a diet high in plant-derived foods may be protective against cancer. One class of plant component under increasing investigation is the phytoestrogens of which there are two main groups: the isoflavones, found mainly in soy products, and the lignans, which are more ubiquitous and are found in fruit, vegetables and cereals with high levels being found in flaxseed. In this study, we have used carefully balanced high-fat (40% energy) diets: a control diet (containing low isoflavone soy protein as the sole protein source), a rye diet (the control diet supplemented with rye bran) and a soy diet (containing as protein source a high isoflavone soy protein). The effect of these diets on the development of colonic cancer was studied in F-344 rats treated with the carcinogen, azoxymethane (two doses of 15 mg/kg given 1 week apart). Colons from treated animals were examined for aberrant crypt foci (ACF) and tumours after 12 and 31 weeks. Results after 12 weeks showed no differences in the total number of ACF in the control, soy or rye bran groups. However, the soy group had increased numbers of small ACF (less than four crypts/focus) while the rye group had decreased numbers of large ACF (greater than six crypts/focus). Examination of colons after 31 weeks gave similar low numbers of ACF in each group with no differences in multiplicity. There were no differences in the number of tumours between the control (1.36 tumours/rat) and soy (1.38 tumours/rat) groups. However, there was a significant decrease in the number of tumours in the rye group (0.17 tumours/rat). These results suggest that soy isoflavones have no effect on the frequency of colonic tumours in this model while rye bran supplementation decreases the frequency of colon cancer. This effect is due not to a decrease in early lesions but in their progression to larger multi-crypt ACF. The study also supports the hypothesis that larger ACF are more predictive of subsequent tumorigenicity.

Animals↗
PubMed1999

Modifying effects of a flavonoid morin on azoxymethane-induced large bowel tumorigenesis in rats.

The modifying effect of dietary exposure to a flavonoid morin during the initiation and post-initiation phases of azoxymethane (AOM)-initiated colorectal carcinogenesis was investigated in male F344 rats. A total of 55 animals were initiated with AOM by weekly s. c. injections of 15 mg/kg body wt for 3 weeks to induce colorectal neoplasms. Rats were fed a diet containing 500 p.p.m. morin for 5 ('initiation feeding') or 28 ('post-initiation feeding') weeks. Other groups contained rats treated with morin alone (500 p.p.m. in diet) and untreated rats. At the end of the study (32 weeks), the incidence of adenocarcinoma in the large intestine of rats initiated with AOM together with (43%) or followed by (29%) a diet containing morin was smaller than that of rats given AOM alone (75%). A significant difference was found between 'post-initiation feeding' and untreated groups (P = 0.023). Although both 'initiation feeding' and 'post-initiation feeding' of morin reduced polyamine levels in colorectal mucosa and blood, 'post-initiation feeding' of morin significantly decreased the proliferating cell nuclear antigen-positive index in aberrant crypt foci. 'Post-initiation feeding' of morin significantly elevated glutathione S-transferase and quinone reductase activities in the liver and large bowel, but 'initiation feeding' caused a significant elevation of these enzymes activities only in the large bowel. These results indicate that morin could exert a weak chemopreventive effect on large bowel tumorigenesis induced by AOM when fed during the post-initiation phase.

Adenocarcinoma↗
PubMed2000

Effects of black tea, green tea and wine extracts on intestinal carcinogenesis induced by azoxymethane in F344 rats.

We investigated whether polyphenolic extracts from black tea, green tea or red wine affect azoxymethane (AOM)-induced intestinal carcinogenesis. Male F344 rats were treated 10 times (1 week apart) with AOM (7.4 mg/kg, s.c.) and then allocated into groups receiving black tea, green tea or red wine extracts mixed in the diet at a dose of 50 mg/kg body weight for 16 weeks. In the rats treated with black tea or wine extracts, there were significantly fewer colorectal tumours than in controls (the mean +/- SE number of tumours/rat was 2.54 +/- 1.6 in controls, 1.54 +/- 1.4 in the black tea group, 3.2 +/- 1.9 in the green tea group and 1.63 +/- 1.6 in the wine extract group). Significantly fewer rats in the black tea and wine extract groups had adenomas than in controls (86%, 59%, 90% and 50% of rats in the control, black tea, green tea and wine extract groups, respectively, had adenomas). The tumours from the black tea group and, to a lesser extent, those from the wine group, had a significantly greater apoptotic index than tumours in controls (mean +/- SE apoptotic index: 2.92 +/- 0.25, 4.13 +/- 0.46, 2.88 +/- 0.30 and 3.72 +/- 0.46 in controls, black tea, green tea or wine extract groups, respectively). In contrast, the apoptotic index of the normal mucosa did not vary among groups. These data indicate that black tea and wine extracts, but not green tea extracts, can protect against AOM-induced colon carcinogenesis by a mechanism probably involving increased apoptosis in tumours.

Adenoma↗
PubMed2000

Expression analysis of the group IIA secretory phospholipase A(2) in mice with differential susceptibility to azoxymethane-induced colon tumorigenesis.

The murine non-pancreatic secretory phospholipase A(2) (sPLA(2)) has been proposed as a tumor modifier of multiple intestinal neoplasia (Min). A genetic polymorphism in the mouse gene that causes a disruption in exon 3 results in loss of functional protein. Mouse strains with a disrupted sPLA(2) gene are susceptible to the Min phenotype and develop numerous intestinal polyps, whereas mice with normal sPLA(2) develop only a limited number of polyps. The following study was undertaken to test the hypothesis that sPLA(2) plays an equivalent role in murine susceptibility to the colon carcinogen azoxymethane (AOM). sPLA(2) status was confirmed by sequencing in mice that are highly susceptible (A/J), susceptible (SWR/J) and resistant (AKR/J) to AOM-induced tumorigenesis. Constitutive expression of sPLA(2) mRNA was compared in small intestine and colon of untreated mice using semi-quantitative RT-PCR. Whereas mRNA expression was nearly absent in A/J mice, AKR/J mice exhibited extensive expression throughout the intestine. Despite the wild-type sPLA(2) gene, colonic mRNA expression in SWR/J mice was significantly lower relative to AKR/J. Immunohistochemical analysis of sPLA(2) protein confirmed the mRNA data. The effect of AOM on colonic sPLA(2) expression was also examined. Twenty-four weeks after the last of six weekly injections of AOM (10 mg/kg i.p.), RT-PCR analysis of distal colons revealed a significant increase in mRNA in normal-appearing epithelium and tumor tissue from AOM-treated mice relative to controls. However, there was no corresponding increase in protein expression in A/J mice. The absence of sPLA(2) expression within control colons of tumor-susceptible A/J mice together with low expression in SWR/J colons is consistent with its potential role as an intestinal tumor modifier, but the carcinogen-induced increase in expression raises doubts as to the significance of sPLA(2) in inhibiting carcinogenesis.

Animals↗
PubMed2000

Chemoprevention studies of the flavonoids quercetin and rutin in normal and azoxymethane-treated mouse colon.

In this study we investigated the chemopreventive effects of quercetin and rutin when added to standard AIN-76A diet and fed to normal and azoxymethane (AOM)-treated mice. Early changes in colonic mucosa were analyzed, including colonic cell proliferation, apoptotic cell death, cyclin D(1) expression and focal areas of dysplasia (FAD). The findings show that the number of colonic epithelial cells per crypt column increased (P: < 0.01) in each normal mouse group fed the flavonoids; AOM administration increased colonic crypt cell proliferation and resulted in a marked rise of bromodeoxyuridine-labeled cells in the lower proliferative zone of the crypt. Both supplementary dietary quercetin and rutin increased the apoptotic index and caused a redistribution of apoptotic cells along the crypt axis in normal mice fed a standard AIN-76A diet. The number of apoptotic cells/column and apoptotic indices markedly increased (P: < 0.01) in the AOM-treated group compared with untreated animals; apoptotic cells expanded throughout the colonic crypts after flavonoid supplementation and AOM administration. Positive cyclin D(1) expression was detected in mice on diets supplemented either with quercetin (P: < 0.01) or rutin (P: < 0.05). AOM administration resulted in the formation of FAD. Both the number of mice exhibiting FAD and the total numer of FAD observed were significantly reduced (P: < 0.01) in AOM-treated animals fed flavonoids compared with mice maintained on the standard AIN-76A diet. Surprisingly, however, quercetin alone was able to induce FAD in 22% of normal mice fed the standard AIN-76A diet.

Animals↗
PubMed2000

Detection of somatic DNA alterations in azoxymethane-induced F344 rat colon tumors by random amplified polymorphic DNA analysis.

Colon carcinogenesis induced in rats by azoxymethane (AOM) is a useful experimental model as it mimics the human adenoma-carcinoma sequence and allows the study of dietary variation and of the effects of chemopreventive substances. Alterations of specific oncogenes and tumor suppressor genes (APC and K-ras) play roles at different stages of this carcinogenesis process. Recently, it has been suggested that genomic instability is the necessary step for the generation of multiple mutations underlying the occurrence of cancer. We studied the frequency of K-ras and microsatellite instability (MSI) in 30 colorectal tumors induced by AOM (30 mg/kg) in F344 rats. We also used the random amplified polymorphic DNA (RAPD) method to identify genomic alterations in chemically induced aberrant crypt foci (ACF), adenomas and adenocarcinomas. K-ras mutations were identified in 16.7% of the cases (5/30; 9% in adenomas and 37.5% in adenocarcinomas) and MSI in 20% (6/30) of the tumors (only one sample exhibited instability at more than one locus). Of 21 primers used for the RAPD assay, six were very informative. All the analyzed tumors (16/16) showed at least one RAPD profile with lost or additional bands compared with the normal mucosa. A lower level of genomic alteration was present in the ACF analyzed (7/10). In conclusion, K-ras and MSI are not often involved in the AOM carcinogenesis in the rat, whereas extensive genomic instability is always present and can be detected using the RAPD analysis.

Adenocarcinoma↗
PubMed2001

Effect of dietary galacto-oligosaccharides on azoxymethane-induced aberrant crypt foci and colorectal cancer in Fischer 344 rats.

The aim of the present study was to investigate the effects of galacto-oligosaccharides (GOS, Elix'or) on the development of aberrant crypt foci (ACF) and colorectal tumours in rats treated with azoxymethane (AOM). Two groups of 102 male Fischer 344 rats were injected twice with AOM to induce colorectal tumours, and fed diets containing either a low [5% (w/w); LGOS] or a high [20% (w/w); HGOS] concentration of GOS. Four weeks after the last AOM injection, 18 animals from each group were killed and their colon was removed for scoring ACF. Half of the animals in the LGOS group were switched to an HGOS diet (L/HGOS) and half of those in the HGOS group to an LGOS diet (H/LGOS). Six weeks after the change in diet, nine animals per group were killed for scoring ACF. Ten months after the start of the study the remaining animals were killed for scoring colorectal tumours. The aberrant crypt multiplicity scored after 13 weeks and the colorectal tumour incidence in rats fed an HGOS diet were significantly lower than those in rats fed an LGOS diet. However, the induction of ACF by AOM, the proliferation rate and apoptotic index of the adenomas, and the size and multiplicity of colorectal tumours were not influenced by the amount of GOS in the diet. The aberrant crypt multiplicity, scored after 13 weeks, was predictive for the tumour outcome at the end of the study. It was concluded that an HGOS diet has a protective effect against the development of colorectal tumours in rats and that this protective effect is exerted during the promotion phase rather than the initiation phase of carcinogenesis.

Animals↗
PubMed2001

Inhibition of azoxymethane-induced colon carcinogenesis in male F344 rats by the citrus limonoids obacunone and limonin.

The modifying effects of dietary administration of the citrus limonoids obacunone and limonin on azoxymethane (AOM)-induced colon tumorigenesis were investigated in two experiments in male F344 rats. In a pilot study, we examined the modifying effects of obacunone and limonin on AOM-induced (20 mg/kg body wt, once a week for 2 weeks) formation of aberrant crypt foci (ACF). Dietary feeding of both compounds at dose levels of 200 and 500 p.p.m. during AOM exposure for 4 weeks ('initiation' feeding) or after AOM treatment for 4 weeks ('post-initiation' feeding) significantly inhibited ACF formation (55-65% reduction by 'initiation' feeding, P < 0.001; 28-42% reduction by 'post-initiation' feeding, P < 0.05-0.002). In a long-term study designed to confirm the protective effects of obacunone and limonin on ACF development, one group was treated with AOM alone and another four groups received the carcinogen treatment plus diets containing 500 p.p.m. test compounds for 3 weeks (initiation phase) or 29 weeks (post-initiation phase). Two groups were treated with obacunone or limonin alone (500 p.p.m. in diet) and one group was maintained on the basal diet. At the termination of the study, dietary exposure to obacunone or limonin during the initiation phase was found to have significantly reduced the incidence of colonic adenocarcinoma (72 versus 25 or 6%, P = 0.004 or 0.00003). Obacunone or limonin feeding during the post-initiation phase also reduced the frequency of colonic adenocarcinoma (72 versus 13%, P = 0.0002). Our results suggest that the citrus limonoids obacunone and limonin might be useful for the prevention of human colon cancers.

Animals↗
PubMed2001

Anatomical site-specific response to DNA damage is related to later tumor development in the rat azoxymethane colon carcinogenesis model.

There is now general agreement that the etiology of proximal and distal colon cancers may differ, thus prompting renewed interest in understanding anatomical site-specific molecular mechanisms of tumor development. Using a 2x2x2 factorial design with male Sprague-Dawley rats (corn oil, fish oil; pectin, cellulose; plus or minus azoxymethane injection) we found a greater than 2-fold difference (P < 0.001) in tumor incidence proximally versus distally (prox/dist ratio: corn oil, 2.25; fish oil, 2.61). The purpose of the present study was to determine if the higher degree of proximal versus distal tumors in our model system could be accounted for by differences between these two sites in initial DNA damage, response to that damage or an effect of diet at one site but not the other. DNA damage was assessed by quantitative immunohistochemistry of O(6)-methylguanine adducts; repair by measurement of O(6)-methylguanine-DNA alkyltransferase and removal was determined by measurement of targeted apoptosis. Although overall initial DNA damage was similar at both sites, in the distal colon there was a greater expression of repair protein (P < 0.001) and a greater degree of targeted apoptosis (P < 0.0001). There was also a reduction in DNA damage in the distal colon of rats consuming fish oil. Together, these results suggest that the lower tumor incidence in the distal colon may be a result of the capacity to deal with initial DNA damage by the distal colon, as compared with the proximal colon. Therefore, the determination of site-specific mechanisms in tumor development is important because distinct strategies may be required to protect against cancer at different sites.

Adenocarcinoma↗
PubMed2001

Slow-release pellets of sodium butyrate do not modify azoxymethane (AOM)-induced intestinal carcinogenesis in F344 rats.

Butyrate exerts anti-tumour effects in vitro, but not consistently in vivo. We previously demonstrated that the administration of slow-release gastro-resistant pellets of sodium butyrate increases apoptosis in the colon mucosa of rats, an effect which may protect against carcinogenesis. Therefore, we studied whether the administration of butyrate pellets could protect rats against experimental colon carcinogenesis. Four to 5 week old male F344 rats were fed a high-fat (HF) diet (230 g/kg corn oil w/w) and treated s.c. with two injections (one week apart) of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight or saline. Rats were then divided into two groups: one group received sodium butyrate pellets mixed into the diet (1.5% w/w) for 33 weeks (150 mg butyrate/day) and the second group received the high-fat diet with no butyrate. Administration of sodium butyrate pellets in the diet did not significantly affect colon carcinogenesis: the number of intestinal tumours/rat was 1.6 +/- 0.2 in controls and 2.1 +/- 0.2 in butyrate-fed rats (means +/- SE; P = 0.22, by ANOVA), while the incidence of intestinal tumours was 79 (23/29) and 90% (27/30) in controls and in butyrate-fed rats, respectively (P = 0.29 by Fisher's exact test). The level of apoptosis in the tumours was not affected by butyrate, nor was the expression of p21(CIP), a cell cycle-related protein. In conclusion, the current study indicates that butyrate does not protect against AOM-induced colon carcinogenesis in rats.

Animals↗