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PubMed1995

Unexpected antagonistic action of 3,2'-dimethyl-4-aminobiphenyl on aberrant crypt induction by 1,2-dimethylhydrazine or azoxymethane in rat colon.

Aberrant crypt foci (ACF) consisting of one more single aberrant crypts (AC) are putative preneoplastic lesions that have been proposed as intermediate biomarkers for colon cancer. Using ACF as the end-point we have studied the effects of two different classes of colon carcinogens, 1,2-dimethylhydrazine dihydrochloride (DMH; 10 or 20 mg/kg body wt/injection) or its metabolite azoxymethane (AOM; 5 mg/kg) and 3,2'dimethyl-4- aminobiphenyl hydrochloride (DMAB; 50 mg/kg) in F344 and Lewis rats. Each carcinogen was given alone or DMH/AOM and DMAB were given in combination in either alternating or successive order in multiple doses. Each compound given alone induced ACF in both rat strains and the effect was most pronounced in the F344 rats. DMAB, not previously tested for ability to induce ACF in rats, was clearly less potent than DMH or AOM. The highest number of ACF was found distally in the colon, independent of treatment or rat strain. Surprisingly, DMAB markedly decreased the carcinogenic effect of DMH, evaluated both as numbers of ACF and AC per colon, as well as number of ACF with four or more AC, when both classes of carcinogens were given alternately. A more pronounced reduction was found in F344 rats than in Lewis rats, being 75-77% and 64-68% respectively with the highest DMH dose. The same tendency was found with successive exposure to DMAB followed by DMH or AOM. These differences in timing of exposure and the different metabolic pathways used by the two classes of carcinogens make a metabolic interaction unlikely as the reason for the antagonistic effect of DMAB on DMH or AOM. The type of standard diet used was found to influence the induction of ACF by the colon carcinogen DMH.

1,2-Dimethylhydrazine↗
PubMed1995

Transgenic expression of human MGMT protects against azoxymethane-induced aberrant crypt foci and G to A mutations in the K-ras oncogene of mouse colon.

Transgenic mice over-expressing MGMT, which codes for the human protein O6-alkylguanine-DNA alkyltransferase, are protected from methylating agent-induced thymic lymphomas. In this study we evaluated the ability of transgenic overexpression of MGMT in the colon to protect mice from the development of azoxymethane(AOM)-induced aberrant crypt foci (ACF) and mutations in K-ras. Colonic alkyltransferase in MGMT+ transgenic mice was > 5-fold higher than in nontransgenics: 10.5 +/- 1.1 vs 2.2 +/- 1.1 fmol/micrograms DNA, P = < 0.0001. Mice received 20 mg AOM/kg i.p. at 6 weeks or 15 mg AOM/kg at 6 and 7 weeks of age, and 8 wks later colons were examined for ACF. A significant protective effect of MGMT was seen in mice given single dose of 20 mg AOM/kg. The incidence of ACF/colon was lower in MGMT+ mice (2.0 +/- 1.2) than in nontransgenic mice (3.9 +/- 1.8, P = 0.02). G to A mutations in codon 12 of K-ras were detected by PCR-RFLP in ACF and in random samples of normal appearing mucosa. The incidence of ACF with mutant K-ras in MGMT transgenic mice (0.6 +/- 0.7/colon) was significantly reduced compared to nontransgenic mice (2.3 +/- 1.7/colon, P = 0.02). We propose that AOM induces at least two overlapping but not identical premalignant lesions (aberrant crypt foci and K-ras mutations) which can be prevented by over-expression of MGMT. Thus, MGMT may protect colonic mucosa from carcinogenesis involving methylating agents such as AOM.

Adenine↗
PubMed1995

Chemoprevention of azoxymethane-induced intestinal carcinogenesis by a novel synthesized retinoidal butenolide, 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone, in rats.

The present study was designed to investigate the modifying effects of dietary 5-hydroxy-4-(2-phenyl-(E)-ethenyl)-2(5H)-furanone (KYN-54), a new synthetic retinoidal butenolide, during the post-initiation phase on azoxymethane (AOM)-induced rat intestinal carcinogenesis. The number of aberrant crypt foci (ACF) in rat colon, colonic ornithine decarboxylase (ODC) activity and bromodeoxy-uridine (BrdUrd) labeling index in rat colonic epithelium were also assessed. At 7 weeks of age, male F344 rats (except the KYN-54 alone and control groups) were given weekly s.c. injections of AOM at 15 mg/kg body wt for 3 weeks. Starting 1 week after the last injection of AOM, rats (except the control group) were fed a diet containing KYN-54 at concentrations of 100 or 200 p.p.m. throughout the experiment. All animals were necropsied at 32 weeks after the start of the experiment. Compared with the AOM alone group, KYN-54 at both doses reduced the incidence and multiplicity of tumors in entire intestine (small and large intestines). In the 200 p.p.m. KYN-54 fed group especially, tumor incidence and multiplicity in the entire intestine were lower compared with the AOM alone group (P < 0.005 and P < 0.05 respectively). Also, the number of ACF/cm2 colon in the groups of rats treated with AOM and KYN-54 at both doses were significantly lower than that of rats treated with AOM alone (P < 0.05). Colonic ODC activity and BrdUrd labeling index in the groups of rats treated with AOM and KYN-54 at both doses were slightly lower than those treated with AOM alone. KYN-54 at 200 p.p.m. significantly lowered BrdUrd labeling index induced by AOM (P < 0.005). These results suggest that KYN-54 might be a promising chemopreventive agent for intestinal neoplasia.

4-Butyrolactone↗
PubMed1996

Azoxymethane enhances ligand-induced activation of EGF receptor tyrosine kinase in the colonic mucosa of rats.

Recent observations suggest that transforming growth factor alpha (TGF-alpha), which binds to the epidermal growth factor (EGF) receptor (EGFR), may induce neoplastic growth of the colonic mucosa through an autocrine mechanism. To assess the functional role of TGF-alpha in colonic carcinogenesis the present investigation examines the changes in TGF-alpha-and EGF-induced activation of intrinsic tyrosine kinase (Tyr-k) activity of EGFR in the colonic mucosa of rats after administration of the colonic carcinogen azoxymethane (AOM; 20 mg/kg body wt). Five days after a single injection of AOM to 4- to 5-month old rats proliferative activity (as assessed by 5-bromo-2'-deoxyuridine immunoreactivity) in the colonic mucosa was increased by approximately 700% over the corresponding saline-injected controls. This was accompanied by: (i) a marked rise in autophosphorylation of a number of mucosal proteins, including one with a M(r) of 170 kDa, a molecular mass that corresponds to EGFR; (ii) a 110-130% increase in basal EGFR Tyr-k activity. Despite this rise in basal EGFR Tyr-k activity, exposure of isolated colonocytes or detergent-solubilized colonic mucosa from AOM-treated animals to either 1 x 10(-8) M TGF-alpha or EGF caused a further 90-160% increase in EGFR Tyr-k activity over the corresponding basal levels. In contrast, bombesin produced no apparent change in EGFR Tyr-k activity. We conclude that increased ligand-induced activation of EGFR Tyr-k may be an important event for development of the hyperproliferative state associated with induction of colorectal neoplasia.

Animals↗
PubMed1996

Inhibitory effects of d-limonene on the development of colonic aberrant crypt foci induced by azoxymethane in F344 rats.

The modifying effect of the monoterpenoid d-limonene in drinking water on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in male F344 rats. The effects of d-limonene intake on ornithine decarboxylase (ODC) activity and on the silver stained nucleolar organizer region protein (AgNOR) count in the colonic mucosa were also estimated. Animals were given 3 weeks s.c. injections of AOM (15 mg/kg body wt) to induce ACF. These rats were treated with or without 0.5% d-limonene in the drinking water, starting 1 week before the first dosing with AOM. All rats were killed 2 weeks after the last AOM injection, to measure the number of ACF, ODC activity and AgNOR count/nucleus in the colon. In rats given AOM and d-limonene the frequencies of ACF and aberrant crypts/colon, and aberrant crypts/focus were significantly decreased compared with those of rats given AOM alone (P < 0.01, P < 0.001 and P < 0.001 respectively). Number of AgNOR counts/nucleus of rats treated with AOM and d-limonene was significantly smaller than that of rats treated with AOM alone (P < 0.001). These results suggest that the monoterpenoid d-limonene might be a chemopreventive agent for colonic carcinogenesis in rats.

Animals↗
PubMed1996

Piroxicam-induced regression of azoxymethane-induced aberrant crypt foci and prevention of colon cancer in rats.

Piroxicam has been shown to prevent azoxymethane (AOM)-induced aberrant crypt foci and colon cancer in rats. In this communication we evaluate whether piroxicam can also cause regression of precancerous lesions identified as aberrant crypt foci, thus preventing the occurrence of cancer. Male Fischer-344 rats were administered 0.125 g/kg piroxicam in their diet starting either 1 week prior to or 12 weeks after a single subcutaneous injection of AOM (30 mg/kg body wt). The yield of aberrant crypt foci and of colon adenomas and adenocarcinomas was determined at 5, 12, 27 and 37 weeks after administering the AOM respectively. When piroxicam was administered starting 1 week prior to AOM the yield of aberrant crypt foci at the three initial time points was reduced. When the administration of piroxicam was delayed until 12 weeks after AOM the yield of aberrant crypt foci was reduced from 53.8 +/- 8.1 foci/colon at 12 weeks to 11.1 +/- 2.0 at 27 weeks. At 37 weeks after administering AOM the yield of colon tumors was 0.59 +/- 0.11 tumors/animal, while in rats administered piroxicam beginning either 1 week prior to or 12 weeks after AOM the yield was similarly reduced to 0.14 +/- 0.07 and 0.17 +/- 0.07 tumors/animal respectively. Thus piroxicam was demonstrated not only to prevent, but also to cause regression of aberrant crypt foci, both of which were associated with the prevention of colon tumors.

Adenocarcinoma↗
PubMed1996

Suppressing effect of perilla oil on azoxymethane-induced foci of colonic aberrant crypts in rats.

We have investigated the modulatory effect of dietary perilla oil which is rich in the n-3 polyunsaturated fatty acid, alpha-linolenic acid, on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats. Animals were given three weekly subcutaneous injections of AOM (15 mg/kg body weight) to induce ACE. The rats were fed a basal diet containing either 12% olive oil, 12% safflower oil, 12% perilla oil, 6% perilla oil plus 6% olive oil, or 3% perilla oil plus 9% olive oil for 5 weeks, starting 1 week before the first dosing of AOM. All rats were sacrificed 2 weeks after the last AOM injection. The amount of food consumed and body weight gain were identical among every dietary group. The frequency of ACF was significantly lower in the rats fed 12% perilla oil than in those fed 12% olive oil or 12% safflower oil (P < 0.01 and P < 0.05, respectively). The suppressive effect of perilla oil was dose-dependent, as the number of ACF was 20.7, 40.7 and 47.4% of those of the 12% olive oil-fed controls in rats fed 12% perilla oil, 6% perilla oil plus 6% olive oil and 3% perilla oil plus 9% olive oil, respectively. Perilla oil significantly reduced ras expression as well as the AgNORs count (cell proliferation biomarkers) in the colonic mucosa, as compared with olive oil or safflower oil (P < 0.01, respectively). Marked increases in n-3 polyunsaturated fatty acids in membrane phospholipid fractions and decreased PGE2 levels were observed in colonic mucosa of perilla oil-fed rats. These results suggest that perilla oil, even in small amounts, suppresses the development of aberrant crypt foci, and is therefore a possible preventive agent in the early stage of colon carcinogenesis.

Animals↗
PubMed1996

Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[a]anthracene-induced mammary cancer in rats.

Curcumin and quercetin were evaluated in rats for their ability to modulate the carcinogenic activity of azoxymethane (AOM) in the colon and 7,12-dimethylbenz[a]anthracene (DMBA) in the mammary gland. In the AOM-induced colon cancer model, male Fischer 344 rats at 8 weeks of age started to receive either curcumin (8 and 16 g/kg) or quercetin (16.8 and 33.6 g/kg) in the diet and 1 week later, were administered AOM (30 mg/kg body wt.) by subcutaneous injection. The animals continued to receive the two agents in the diet until sacrificed 45 weeks later. Curcumin mediated a dose-dependent inhibition of the incidence and multiplicity of adenomas from 47% and 0.58 +/- 0.12 adenomas/rat in the AOM-treated control group to 19% and 0.22 +/- 0.08 and 0.06% and 0.08 +/- 0.06 adenomas/rat for the low and high dose groups, respectively. A low yield of adenocarcinomas (0.06 +/- 0.04 adenocarcinomas/rat) was induced by AOM which was not significantly altered by curcumin. Treatment with quercetin caused a dose-dependent increase in the yield of AOM-induced tumors in the colon from 0.06 +/- 0.04 adenocarcinoma/rat to 0.64 +/- 0.12 and 1.14 +/- 0.17 for the low and high dose groups, respectively. In the DMBA-induced mammary cancer model, curcumin or quercetin was administered at either 10 or 20 g/kg diet, beginning 7 days prior to DMBA and continually throughout the remainder of the experiment. Neither curcumin nor quercetin significantly altered the incidence of animals with tumors or the tumor multiplicity, while the high concentration of both agents significantly increased tumor latency. These results demonstrate different responses to these agents in the two models. While curcumin was highly effective as a chemopreventive agent in the colon model, it was only weakly effective in the mammary model. In contrast, quercetin which was also only weakly effective in the mammary model, caused a dose-dependent enhancement of tumors induced by AOM in the colon model.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Synergistic suppression of azoxymethane-induced foci of colonic aberrant crypts by the combination of beta-carotene and perilla oil in rats.

The modulating effect of the combined dietary feeding of beta-carotene and perilla oil, which is rich in alpha-linolenic acid, on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in male F344 rats. Rats received oral administration of beta-carotene (0, 50 or 200 mg/kg body weight/day) and fed a basal diet containing either 12% olive oil, 3% perilla oil plus 9% olive oil, or 12% perilla oil. A dose-dependent suppressive effect of perilla oil was found. The numbers of ACF were 42.0 and 18.4% of those of the 12% olive oil-fed controls in the rats fed 3% perilla oil plus 9% olive oil and 12% perilla oil, respectively. The development of ACF was also reduced significantly by the addition of dietary beta-carotene in each of the oil-fed groups (P < 0.05, respectively). The suppression by the combination of beta-carotene and perilla oil was synergistic, as the numbers of ACF were 12.9 and 8.9% of those of the 12% olive oil-fed controls in beta-carotene-treated rats fed 3% perilla oil plus 9% olive oil and 12% perilla oil, respectively. beta-carotene plus perilla oil also suppressed the numbers of silver-stained nucleolar organizer regions and the expression of ras mRNA in the colonic mucosa (cell proliferation biomarkers). Following administration of beta-carotene, a significant increase in the concentration of intact beta-carotene molecules was found in the colonic mucosa, livers, and sera. However, no accumulation of retinoids was observed in the colonic mucosa, suggesting that the inhibitory effect may not be related to the provitamin A activity. These results suggest that the combination of beta-carotene and perilla oil may be useful in the prevention of colon cancer.

Administration, Oral↗
PubMed1997

Dietary polyamines promote the growth of azoxymethane-induced aberrant crypt foci in rat colon.

We have examined whether dietary polyamines influence the formation and initial growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rat colon. Effects of a combination of dietary polyamines at three dose levels (putrescine: 50, 280, 740 nmol/g; spermidine: 10, 261, 763 nmol/g; spermine: 1, 31, 91 nmol/g) in the polyamine-poor AIN-76A diet were studied in animals in two different experimental situations: animals treated with AOM alone and animals treated with AOM + difluoromethylornithine (DFMO), a specific inhibitor of endogenous polyamine synthesis. In both experimental situations, dietary polyamines enhanced the growth of ACF, expressed as the number of large ACF (foci with three or more aberrant crypts, ACF > or = 3), whereas the formation of ACF, expressed as the number of ACF, was apparently not altered. In animals treated with AOM alone, maximal growth enhancing effect on ACF was nearly obtained with the median level of dietary polyamine. In rats fed a low polyamine diet, basic AIN-76A, DFMO reduced the growth of AOM-induced ACF by 83%. This inhibitory effect of DFMO was counteracted by dietary polyamines in a dose-dependent manner, and it was abolished at the highest level of polyamines. In conclusion, it was demonstrated that dietary polyamines are able to enhance the growth of AOM-induced ACF. Further, dietary polyamines reversed the DFMO-caused inhibition of ACF growth, probably by compensating for the DFMO-reduced endogenous polyamine synthesis.

Animals↗
PubMed1997

Interactive suppression of aberrant crypt foci induced by azoxymethane in rat colon by phytic acid and green tea.

Several epidemiological studies point to a strong correlation between nutrient composition of the diet and cancer of the colon. Phytic acid, present in grains, has been credited with reducing the risk of cancer of the colon. A number of reports are available indicating the benefits of green tea consumption in reducing the risk of stomach, lung and skin cancer, but little data are available on the effect of green tea in reducing the risk of colon cancer. Also, there are no studies on the combined effect of these compounds on colon tumorigenesis. Thus the primary objective of this investigation was to elucidate the combined effects of green tea and phytic acid on colonic preneoplastic lesions and the Phase II enzyme glutathione S-transferase. Fisher 344 male weanling rats were divided into nine groups of 15 rats each and fed the experimental diet for 13 weeks. Rats received two s.c. injections of azoxymethane in saline at 16 mg/kg body wt at 7 and 8 weeks of age. Rats received three levels (0, 1 and 2%) of phytic acid with three levels (0, 1 and 2%) of green tea within each phytic acid level in a 3 x 3 factorial experiment. Results indicate that while green tea had a marginal effect (P < 0.14), phytic acid significantly reduced the incidence of aberrant crypt foci (P < 0.008). The interaction between green tea and phytic acid was significant (P < 0.029 for distal and < 0.0168 for entire colon) and positive, pointing to a synergistic effect of green tea and phytic acid.

Analysis of Variance↗
PubMed1997

Prevention by retinoids of azoxymethane-induced tumors and aberrant crypt foci and their modulation of cell proliferation in the colon of rats.

Retinoids are proposed chemopreventive agents that inhibit cell proliferation and induce differentiation. Their ability to prevent azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors and to modulate cell proliferation was investigated in the colon of male F344 rats. Thirteen retinoids were evaluated for prevention of ACF and two of them, 9-cis-retinoic acid (RA) and 4-(hydroxyphenyl)retinamide (4-HPR), were also evaluated for prevention of colon cancer. The retinoids were administered continuously in the diet starting 1 week prior to the first of two weekly 15 mg/kg i.p. injections of AOM and for a total of either 5 or 36 weeks in order to evaluate their effect on colonic ACF and tumors. At a concentration of 1 mmol/kg diet, 2-(carboxyphenyl)retinamide caused the greatest reduction (57.7%) in the yield of ACF. 9-cis-RA was toxic at 1 mmol/kg so that it was evaluated at 0.1 mmol/kg, resulting in a 41.6% reduction in ACF. The ability of the retinoids to reduce the proliferating cell nuclear antigen (PCNA) labeling index in ACF and in non-involved crypts correlated with their ability to prevent ACF. Both 9-cis-RA (0.1 and 0.2 mmol/kg diet) and 4-HPR (1 and 2 mmol/kg diet) were highly effective in decreasing the yield of AOM-induced colon tumors. In summary, retinoids were demonstrated to reduce cell proliferation and to prevent ACF and tumors in the colon, suggesting promise as preventive agents for colon cancer.

Alitretinoin↗
PubMed1997

Bifidobacterium longum and lactulose suppress azoxymethane-induced colonic aberrant crypt foci in rats.

Bifidobacterium longum has been shown to afford protection against colon tumorigenesis. Lactulose, a keto analog of lactose, serves as a substrate for preferential growth of Bifidobacterium. It is not known whether feeding lactulose along with B. longum will have any advantage over feeding of B. longum alone. To test this combination effect, 61 male Fisher 344 weanling rats were divided into four groups of 15 rats each (16 in the control group) and assigned to one of the following four diets for 13 weeks: (i) AIN76A (control, C); (ii) C + 0.5% B. longum (C+Bl, containing 1 x 10(8) viable cells/g feed); (iii) C + 2.5% lactulose (C+L); (iv) C + 0.5% B. longum + 2.5% lactulose (C+Bl+L). All animals received a s.c. injection of azoxymethane at 16 mg/kg body wt at 7 and 8 weeks of age. Colons of 10 rats from each dietary group were analyzed for aberrant crypt foci (ACF), which are preneoplastic markers. Colonic mucosa and livers from five rats were analyzed for glutathione S-transferase (GST, a Phase II enzyme marker). Results indicate that feeding of lactulose and B. longum singly and in combination reduces the number of ACF (P = 0.0001) and the total number of aberrant crypts significantly (P = 0.0005). The total number of ACF in diets C, C+Bl, C+L and C+Bl+L were 187 +/- 9, 143 +/- 9, 145 +/- 11 and 97 +/- 11 respectively. There was no significant difference in weight gain among treatments. Colonic mucosal GST levels were significantly (P = 0.05) higher in the Bl and L groups compared with group C. Initially there was a mild diarrhea in lactulose-fed rats. There was a positive correlation between higher cecal pH and number of ACF. Results of the study indicate that Bifidobacterium and lactulose exert an additive antitumorigenic effect in rat colon.

Animal Feed↗
PubMed1997

A xanthine oxidase inhibitor 1'-acetoxychavicol acetate inhibits azoxymethane-induced colonic aberrant crypt foci in rats.

The modifying effect of dietary administration of a xanthine oxidase inhibitor 1'-acetoxychavicol acetate (ACA) present in an edible plant Languas galanga in Thailand on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in rats. Male F344 rats were given s.c. injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce colonic ACF. They were fed the diets containing 100 or 200 ppm ACA for 5 weeks, starting 1 week before the first dosing of AOM. At the termination of the study (week 5), AOM induced 118 +/- 28 ACF/colon. Dietary administration of ACA caused significant reduction in the frequency of ACF (41% inhibition by 100 ppm ACA feeding and 37% inhibition by 200 ppm ACA feeding, P<0.01). Such inhibition might be associated with suppression of the proliferation biomarkers' expression such as ornithine decarboxylase activity in the colonic mucosa, number of silver-stained nucleolar organizer regions' protein in the colonic mucosal cell nuclei and blood polyamine content. These results indicate that ACA could inhibit the development of AOM-induced ACF through its suppression of cell proliferation in the colonic mucosa and ACA might be a possible chemopreventive agent against colon tumourigenesis.

Animals↗
PubMed1997

Inhibitory effects of lemon grass (Cymbopogon citratus Stapf) on formation of azoxymethane-induced DNA adducts and aberrant crypt foci in the rat colon.

The 80%-ethanol extract of lemon grass (Cymbopogon citratus Stapf), a medicinal plant in Thailand, has been reported to be antimutagenic against various known mutagens in the Salmonella mutation assay. To investigate chemoprevention in an animal carcinogenesis model, we examined inhibitory effects of the lemon grass extract on the formation of azoxymethane (AOM)-induced DNA adducts and aberrant crypt foci (ACF) in the rat colon. One week after the start of the treatment with lemon grass extract at doses of 0.5 or 5 g/kg body wt by gavage, F344 rats received two s.c. injections of 15 mg of AOM per kg body weight at 1 week apart. For DNA adduct analysis of the colon and liver, the rats were killed 12 h after the second AOM injection. The DNA from the liver and colon were used for O6-methylguanine and N7-methylguanine analysis. For ACF analysis in the initiation stage, AOM-injected rats were continuously treated with lemon grass extract and were killed 3 weeks after the second AOM injection. For analysis in the promotion stage the treatment with the lemon grass extract (0.5 g/kg) started 2 weeks after the second AOM injection and continued for 12 weeks until the animals were killed. Lemon grass treatment significantly inhibited DNA adduct formation in both the colonic mucosa and the muscular layer but not in the liver. In addition, lemon grass extract treatment significantly inhibited ACF formation in both the initiation stage and the promotion stage. Especially in the promotion stage, lemon grass treatment inhibited the formation of larger ACF (with four or more crypts per focus), which was predictive of tumor incidence. Furthermore, lemon grass extract inhibited fecal beta-glucuronidase competitively and had antioxidant activity. These results suggest that the lemon grass extract inhibits the release of activated aglycon, methylazoxymethanol, from a glucuronide conjugate in the colon, and decreases the DNA adducts and ACF formation in the rat colon.

Animals↗
PubMed1997

Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin.

The modulating effects of dietary feeding of two flavonoids, diosmin and hesperidin, both alone and in combination, during the initiation and post-initiation phases 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 to induced colon neoplasms. Rats were fed the diets containing diosmin (1000 ppm), hesperidin (1000 ppm) or diosmin (900 ppm) + hesperidin (100 ppm) for 5 weeks (initiation treatment) or 28 weeks (post-initiation treatment). The others contained the groups of rats treated with diosmin, hesperidin alone or in combination, and untreated. At the end of the study (32 weeks), the incidence and multiplicity of neoplasms (adenoma and adenocarcinoma) in the large intestine of rats initiated with AOM together with, or followed by, a diet containing diosmin or hesperidin were significantly smaller than those of rats given AOM alone (P <0.001). The combination regimen during the initiation and post-initiation stages also inhibited the development of colonic neoplasms, but the tumor data did not indicate any beneficial effect of diosmin and hesperidin administered together as compared with when these agents were given individually. In addition, feeding of diosmin and hesperidin, both alone and in combination, significantly inhibited the development of aberrant crypt foci. As for cell proliferation biomarkers, dietary exposure of diosmin and hesperidin significantly decreased the 5'-bromodeoxyuridine-labeling index and argyrophilic nuclear organizer region's number in crypt cells, colonic mucosal ornithine decarboxylase activity, and polyamine levels in the blood. These results indicate that diosmin and hesperidin, both alone and in combination, act as a chemopreventive agent against colon carcinogenesis, and such effects may be partly due to suppression of cell proliferation in the colonic crypts, although precise mechanisms should be clarified.

Animals↗
PubMed1997

Suppression of azoxymethane-induced rat colon carcinoma development by a fish oil component, docosahexaenoic acid (DHA).

The effects of intragastric gavage administration of docosahexaenoic acid (DNA) , a major component of fish oil, on azoxymethane (AOM)-induced colon carcinogenesis in rats was investigated. Male F344 rats were treated with 15 mg/kg body wt of AOM once a week, for two weeks. The animals were given either 1 ml of DHA or water intragastrically 5 times a week, starting the day before the first carcinogen treatment. The numbers of AOM-induced aberrant crypt foci in the rats given DHA were 76% and 62% of the control values, at 4 and 12 weeks, respectively. After 36 weeks of DHA treatment, colon tumors were counted and examined histologically. The blood plasma levels of prostaglandin E2 (PGE2) and polyunsaturated fatty acids were also quantified. The incidences of colon cancer did not differ, being 96% and 92% in the AOM and AOM+DHA groups, respectively. Colon cancer multiplicity was, however, significantly decreased by the DHA treatment; 3.65 +/- 2.18 in the AOM group and 2.41 +/- 1.58 in the AOM+DHA group (P <0.01). Notably, the numbers of moderately differentiated adenocarcinomas in the middle and distal colon in the DHA-treated group were lower than in the AOM group. The levels of PGE2 and arachidonic acid in the blood plasma of DHA-treated rats were also significantly lower than in the AOM group. These results suggest that DHA exerts its inhibitory effect on colon carcinogenesis by modulating lipid metabolism and inhibiting the arachidonic cascade.

Animals↗
PubMed1998

Effect of black tea on azoxymethane-induced colon cancer.

Two sets of experiments on the role of tea in azoxymethane (AOM) induced colon cancer were performed. The first test involved male F344 rats given 1.25% solutions of black tea beginning at 5 weeks of age and ending at 51 days of age. At 6 and 7 weeks of age, they received 15 mg/kg AOM and were held for 50 weeks. Another group received the AOM dosage at 6 and 7 weeks and were placed on the tea solutions 2 days after the last AOM dosage, at 51 days of age, and held for the 50-week period. The end point was the occurrence and multiplicity of colon cancer, classified as in situ, exophytic, invasive and Peyer's patch carcinomas. Tea failed to affect the incidence and multiplicity of colon cancers when given during or after the AOM administration, but tea after AOM increased the multiplicity of exophytic carcinomas. In a second series of tests, solutions of 0.6, 1.25, 1.75 or 2.5% tea were given, beginning 1 week prior to the two AOM doses and extending for 42 weeks. Also, one group received 1.25% tea and 1.85% whole milk. The incidence of exophytic or invasive colon cancer and tumor multiplicity were similar in all treatment groups, although the incidence of exophytic neoplasms was higher with 2.5% tea. Thus, chronic administration failed to significantly change the incidence and multiplicity of the AOM-induced colon cancers. These findings are accounted for by the underlying mechanism, namely the fact that tea solutions do not alter the amount of cytochrome P-4502E1 required for the metabolic activation of AOM.

Animals↗