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PubMed1987

Chemoprevention of colon carcinogenesis by dietary organoselenium, benzylselenocyanate, in F344 rats.

The effect of feeding benzylselenocyanate (BSC) and its sulfur analogue, benzylthiocyanate (BTC), 2 wk before, during, and until 1 wk after carcinogen administration (initiation phase) on intestinal carcinogenesis induced by azoxymethane (CAS:25843-45-2) was studied in male F344 rats. Weanling rats were raised on a semipurified diet (AIN-76A diet; control diet). Beginning at 5 wk of age, groups of animals consuming the control diet were fed one of the diets containing 25 ppm BSC or BTC. An additional group was continued on the control diet. At 7 wk of age, all animals in 3 groups, except the vehicle-treated controls, were administered s.c. injections of azoxymethane (15 mg/kg body weight, once weekly for 2 wk). Animals were continued on the control diet and BSC and BTC diets until 1 wk after carcinogen treatment, when those groups receiving BSC and BTC diets were fed the control diet until termination of the experiment. Tissue and blood plasma glutathione peroxidase activity was measured in vehicle-treated animals fed the control diet and BSC and BTC diets for 5 wk. The results indicate that body weights were comparable among the various dietary groups. BSC in the diet significantly inhibited the incidence (percentage of animals with tumors) and multiplicity (tumors/animal) of adenocarcinomas in the colon and multiplicity of adenocarcinomas in the small intestine compared to those fed the control diet. BTC in the diet had no effect on colon and small intestinal tumors. Selenium-dependent glutathione peroxidase activity was significantly increased in kidneys and colon and small intestinal mucosae of animals fed the BSC diet compared to animals fed the BTC and control diets.

Administration, Oral↗
PubMed1995

Enhancement of experimental colon carcinogenesis by dietary 6-phenylhexyl isothiocyanate.

Naturally occurring and related synthetic isothiocyanates are known to exert chemopreventive effects in several organs in rodent models. The present study was designed to investigate the efficacy of 6-phenylhexyl isothiocyanate (PHITC), a potent chemopreventive agent in the lung tumor model in strain A mice, on azoxymethane-induced colon tumorigenesis. Another aim was to study the modulating effect of PHITC on colonic mucosal and tumor phospholipase A2 (PLA2), phosphatidylinositol-specific phospholipase C (PI-PLC), lipoxygenase (LOX), and cyclooxygenase (COX) activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 320 or 640 ppm of PHITC representing 40 and 80% maximum tolerated dose levels, respectively. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All animals continued on their respective dietary regimen for 52 weeks after the carcinogen treatment; then the study was terminated. Colonic mucosa and tumors were analyzed for PLA2, PI-PLC, prostaglandin (PG) E2, COX, and LOX activities. Intestinal tumors were evaluated histopathologically and classified as invasive or noninvasive adenocarcinomas. Intestinal tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal; tumors/tumor-bearing animal) were compared among the dietary groups. At the 640-ppm dose level, dietary PHITC significantly increased the incidence of intestinal (small intestine plus colon) adenocarcinomas (P < 0.05) as well as the multiplicities of invasive and noninvasive adenocarcinomas of the colon (P < 0.05 to 0.01). At the 320-ppm dose level, PHITC increased the multiplicity (tumors/animal) of noninvasive adenocarcinomas and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05). Dietary PHITC also increased the colon tumor volume (2- to 4.3-fold) in a dose-dependent manner. Moreover, PHITC significantly enhanced the activities of PLA2 (50-100%) and levels of PGE2 (2-fold) in the colonic mucosa and in tumors, but it had no significant effect (P > 0.05) on PI-PLC activity. The formation of COX metabolites, particularly PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2, as well as LOX metabolites such as 8(S)-, 12(S)- and 15 (S)-hydroxyeicosatetraenoic acids, were significantly increased in the colonic mucosa and tumors of animals that were fed 640 ppm of PHITC. Although the exact mechanism by which PHITC promotes colon tumorigenesis remains to be elucidated, it is likely that the tumor-promoting effects of PHITC may, at least in part, be related to increased eicosanoid metabolism in the colon.

Animals↗
PubMed1995

Chemoprevention of colon carcinogenesis by phenylethyl-3-methylcaffeate.

Previous studies from this laboratory have established that caffeic acid esters present in propolis, a natural resin produced by honey bees, are potent inhibitors of human colon adenocarcinoma cell growth, carcinogen-induced biochemical changes, and preneoplastic lesions in the rat colon. The present study was designed to investigate the chemopreventive action of dietary phenylethyl-3-methylcaffeate (PEMC) on azoxymethane-induced colon carcinogenesis and to examine the modulating effect of PEMC on phosphatidylinositol-specific phospholipase C (PI-PLC), phospholipase A2, lipoxygenase (LOX), and cyclooxygenase activities in the colonic mucosa and tumor tissues in male F344 rats. At 5 weeks of age, groups of rats were fed the control (modified AIN-76A) diet, or a diet containing 750 ppm of PEMC. At 7 weeks of age, all animals except those in the vehicle (normal saline)-treated groups were given 2 weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All groups were maintained on their respective dietary regimen until the termination of the experiment 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Both colonic mucosa and tumors were analyzed for PI-PLC, phospholipase A2, cyclooxygenase, and LOX activities. The results indicate that dietary administration of PEMC significantly inhibited the incidence and multiplicity of invasive, noninvasive, and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05-0.004). Dietary PEMC also suppressed the colon tumor volume by 43% compared to the control diet. Animals fed the PEMC diet showed significantly decreased activities of colonic mucosal and tumor PI-PLC (about 50%), but PEMC diet had no effect on phospholipase A2. The production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the LOX pathway from arachidonic acid was reduced in colonic mucosa and tumors (30-60%) of animals fed the PEMC diet as compared to control diet. PEMC had no effect on the formation of colonic mucosal cyclooxygenase metabolites but inhibited the formation in colonic tumors by 15-30%. The precise mechanism by which PEMC inhibits colon tumorigenesis remains to be elucidated. It is likely that the chemopreventive action may be related, at least in part, to the modulation of PI-PLC-dependent signal transduction and LOX-mediated arachidonic acid metabolism.

Animals↗
PubMed1995

Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound.

Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phospholipase C gamma 1, ex vivo prostaglandin (PG) E2, cyclooxygenase, and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus noninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also significantly suppressed the colon tumor volume by > 57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%) and levels of PGE2 (> 38%). The formation of prostaglandins such as PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.

Animals↗
PubMed1993

Effects of caloric restriction and dietary fat on epithelial cell proliferation in rat colon.

Epidemiological studies indicate that caloric intake and dietary fat content influence colonic carcinogenesis. In rodents, caloric restriction reduces, and some fats increase, carcinogen-induced colon cancer incidence. The present study was designed to investigate the effects of caloric restriction on colonic cell proliferation (CCP) in carcinogen-treated or control rats fed low- or high-fat diets. F344 rats were treated with azoxymethane (15 mg/kg x2) and then fed an isocaloric AIN 76A diet containing either 5 or 23% corn oil, ad libitum or calorie-restricted to 70 or 80% of the kilocalories consumed by ad libitum rats. Biopsies of the distal colon were taken at 10 and 20 weeks, and rats were sacrificed at 21 or 34 weeks on the experimental diets. Distal CCP was determined by microautoradiography after [3H]thymidine labeling in vitro or presacrifice administration in vivo. The labeling index and number of labeled cells per crypt column were significantly reduced by caloric restriction at all time points (10, 20, 21, 34 weeks). Caloric restriction reduced CCP in high fat- and low fat-fed rats and in azoxymethane-treated and control rats. High fat resulted in decreased CCP in the distal colon compared to low fat at 34 weeks but not earlier. The findings indicate that: (a) caloric restriction is effective in favorably modulating CCP, an intermediate biomarker of colon cancer risk; (b) a high fat ad libitum diet, which increased tumor yield, does not increase distal colon proliferation; (c) dietary fat intake alters proliferation in a manner differing from that induced by changing dietary caloric intake.

Animals↗
PubMed1996

Evaluation of cyclooxygenase-2 inhibitor for potential chemopreventive properties in colon carcinogenesis.

Epidemiological and laboratory studies indicate an inverse relationship between the risk of colon cancer development and intake of nonsteroidal antiinflammatory agents, including aspirin. One of the mechanisms by which nonsteroidal antiinflammatory agents inhibit colon carcinogenesis is through the inhibition of prostaglandin production by cyclooxygenase isozymes (COX-1 and COX-2). Overexpression of COX-2 has been observed in colon tumors. Thus, selective inhibitors of COX-2 could potentially serve as chemopreventive agents. We have assessed the chemopreventive properties of SC-58635, a COX-2 inhibitor, and of sulindac, as a positive control, in a double-blind study, using azoxymethane-induced colonic aberrant crypt foci (ACF) as a measure of efficacy. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 150 or 1500 ppm SC-58635, 320 ppm sulindac, or 1500 ppm placebo. Two weeks later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with azoxymethane (15 mg/kg of body weight, once weekly for 2 weeks). At 16 weeks of age, all rats were sacrificed and colons were evaluated for ACF. As expected, dietary administration of sulindac suppressed ACF development as such and reduced crypt multiplicity in terms of number of aberrant crypts/ focus. Administration of 1500 ppm SC-58635 inhibited total ACF induction and crypt multiplicity by about 40-49%. Our finding that SC-58635 significantly suppressed colonic ACF formation and crypt multiplicity strengthens the hypothesis that a selective COX-2 inhibitor possesses chemopreventive activity against colon carcinogenesis.

Animals↗
PubMed1996

Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat.

We assessed the effects of 41 potential chemopreventive agents in the F344 rat using the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon as the measure of efficacy. ACF were induced by the carcinogen azoxymethane in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last azoxymethane injection, animals were evaluated for the number of aberrant crypts detected in methylene blue-stained whole mounts of rat colon. The 41 agents were derived from a priority listing that was based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. The list of agents included representative examples of phytochemicals, vitamins, minerals, inhibitors of proliferation, inducers of Phase 1 and Phase 2 metabolism systems, nonsteroidal anti-inflammatory agents, and differentiation agents. Eighteen agents were positive in the assay, significantly reducing the incidence of ACF at least in one of two doses tested. As a chemical class, the nonsteroidal anti-inflammatory drugs, which included ibuprofen, ketoprofen, piroxicam, and indomethacin, were most active; other less potent agents were arginine, butylated hydroxyanisole, curcumin, diallyl sulfide, difluoromethylornithine, 18 beta-glycyrrhetinic acid, indole-3-carbinol, oltipraz, purpurin, rutin, and the sodium salts of butyrate, selenite, and thiosulfate. Twenty-three agents did not inhibit ACF; included among these were several agents that promoted the development of ACF at one or both doses tested: benzyl isothiocyanate,calcium glucarate, catechin, dihydroepiandosterone, fluocinolone acetonide,folic acid, levamisole, 2-mercaptoethanesulfonic acid, nordihydroguiaretic acid, potassium glucarate, propyl gallate, beta-sitosterol, sodium cromolyn, sodium molybdate, and sulfasalazine. The aberrant crypt assay demonstrates reasonable specificity and sensitivity in predicting which agents are likely to prevent colon cancer.

Animals↗
PubMed1998

Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis.

Epidemiological and laboratory studies suggest that nonsteroidal antiinflammatory drugs reduce the risk of colon cancer and that the inhibition of colon carcinogenesis is mediated through modulation of prostaglandin production by cyclooxygenase (COX) isozymes (COX-1 and -2). Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 activity could potentially serve as chemopreventive agents. Our recent study indicated that celecoxib (SC-58635), a specific COX-2 inhibitor, suppressed colonic aberrant crypt foci formation induced by azoxymethane in rats and led us to investigate more specifically the chemopreventive potential of this compound using colon tumors as end points. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or an experimental diet containing 1500 ppm celecoxib. Two weeks later, all animals except those in the saline-treated groups received s.c. injections of azoxymethane (15 mg/kg of body weight) once weekly for 2 weeks. All groups were kept on their regimen until the experiment was terminated, 50 weeks after carcinogen treatment. Colon tumors were evaluated histopathologically. Remarkably, dietary administration of celecoxib inhibited both incidence and multiplicity of colon tumors by about 93 and 97%, respectively. It also suppressed the overall colon tumor burden by more than 87%. The degree of tumor inhibition was more pronounced with celecoxib than it was with previously evaluated nonsteroidal anti-inflammatory drugs. The results of this study provide evidence, for the first time, that a specific COX-2 inhibitor, celecoxib, possesses strong chemopreventive activity against colon carcinogenesis.

Animals↗
PubMed1998

Enrichment of the more hydrophilic bile acid ursodeoxycholic acid in the fecal water-soluble fraction after feeding to rats with colon polyps.

We recently showed that feeding the cytoprotective bile acid ursodeoxycholic acid (UDCA) to rats resulted in significant reduction in polyps and especially cancers, both in number and size (D. L. Earnest et al., Cancer Res., 54: 5071-5074, 1994). Because fecal secondary bile acids [particularly deoxycholic acid (DCA)] are considered to promote formation of colon adenomas and cancer, we have now attempted to find a relationship between polyp reduction and fecal secondary bile acids after feeding UDCA to these rats. We examined the fecal bile acids in rats with polyps and compared them with fecal bile acids in control rats and also determined the bile acid composition in fecal aqueous phase, which is in direct contact with the colon epithelium and may be physiologically more active. Treatment with azoxymethane did not significantly alter fecal bile acid composition in the rats. Cholic acid feeding resulted in greatly increased proportions of DCA (82% of total bile acids versus 18% in control rats). On the other hand, UDCA feeding significantly reduced the proportion of fecal DCA (2% in control rats fed UDCA and 3% in rats also treated with azoxymethane). In control rats, 96% of the bile acids were present in the water-insoluble fraction and 4% in the water-soluble fraction. The major insoluble bile acids included DCA and hyodeoxycholic acid (73% of total bile acids). In contrast, the muricholic acids were concentrated in the soluble fraction (37%). When 0.4% UDCA was added to the diet, lithocholic acid increased in the insoluble fraction (40 versus 1%), but the hydrophilic UDCA and muricholic acids were enriched in the water-soluble fraction (37 and 43%, respectively). Thus, the hydrophobic bile acids were distributed predominantly in the water-insoluble fraction, whereas the hydrophilic bile acids were distributed preferentially in the water-soluble fraction. These data suggest that UDCA may prevent colon tumors and polyps by countering the toxic effect of DCA and enhancing the possible cytoprotective effects of UDCA and muricholic acids in the water-soluble fraction in the feces of rat.

Animals↗
PubMed1995

Evidence for ras gene mutation in 2-amino-3-methylimidazo[4,5-f]quinoline-induced colonic aberrant crypts in the rat.

Aberrant crypt foci (ACF) are putative preneoplastic lesions that develop after treatment of animals with colon carcinogens, including cooked-meat heterocyclic amines such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Male F344 rats given IQ by gavage on alternating days for 2 wk (130 mg/kg body weight) and killed 12 wk after the final carcinogen dose had an average of 4.4 ACF/colon and an average of 3.2 crypts/focus. The DNA from these ACF was amplified by the polymerase chain reaction and analyzed by 3'-primer mismatch and direct sequencing methods for mutations in the Ki-ras proto-oncogene. Of the 37 IQ-induced ACF screened, three contained a GGT-->GAT mutation in codon 12 and one contained a GGC-->GCC mutation in codon 13. The approximately 11% frequency of mutation in IQ-induced ACF is within the range of previous ACF studies of azoxymethane, which reported a 7-37% incidence of Ki-ras mutation. These findings suggest that for both compounds, ras mutations occur during early stages of colorectal tumorigenesis. However, while ras mutations can be detected with increasing frequency in azoxymethane-induced adenomas and carcinomas, they are reportedly absent in IQ-induced colon tumors. Thus, for IQ and related compounds additional factors (possibly increased cell proliferation) may be important in the later stages of colorectal tumorigenesis.

Animals↗
PubMed1986

Growth characteristics of autochthonous experimental colonic tumors as assessed by serial colonoscopic measurement in rats.

We report the growth characteristics of autochthonous experimental colonic tumors as assessed by serial measurements at colonoscopy. Male Fischer 344 rats were given 10 weekly subcutaneous injections of the bowel carcinogen azoxymethane, 10 mg/kg (weeks 1-10). Beginning in week 15, colonoscopy to the splenic flexure was performed weekly with a pediatric fiberoptic bronchoscope. Width of identified tumors was measured in photographs that included a scale passed through the biopsy channel, and tumor volume was calculated using computerized image analysis. Sensitivity, specificity, predictive values, and efficiency of colonoscopy for identification of tumors were 85%-100%. Cumulative tumor incidence in the descending colon increased in a relatively linear fashion from 3% at week 15 to 68% at week 30. Tumor width by colonoscopy correlated well with width at necropsy (r = 0.951). Growth curves of individual tumors were highly variable; however, tumor width showed stable mean weekly growth rates. By contrast, mean calculated tumor volume rose exponentially, with deviation from the fitted curve in the sixth week. All tumors greater than 3 mm in width or greater than 10 mm3 in volume showed invasion. Final tumor width and volume, and growth of tumor volume during the initial week but not the later weeks of observation, correlated with depth of invasion. Our findings suggest that colonoscopic measurement was useful to study the growth characteristics of autochthonous experimental colonic tumors; azoxymethane administration produced persistently altered colonic epithelium that had variable latent periods until development of visible tumors in individual rats; the growth curves of individual colonic tumors were exponential, although variable, during the initial weeks; invasion was found in small tumors and depth of invasion correlated with growth rate during the initial week but not the later weeks. This aggressive behavior of the tumors early in their course contrasts with colorectal adenomas in humans and argues against the routine occurrence of an adenoma-carcinoma sequence in the model we used.

Animals↗
PubMed1998

Evaluation of omeprazole genotoxicity in a battery of in vitro and in vivo assays.

Omeprazole, a proton pump inhibitor of wide use in the treatment of gastric acid-related disorders, was evaluated for its genotoxic effects in both rat and human cultured cells and in the intact rat. DNA repair synthesis, as revealed by autoradiography, was detected in primary cultures of metabolically competent rat hepatocytes exposed to concentrations ranging from 10 to 100 mg/l, but the responses cannot be considered as clearly positive. Under the same experimental conditions any significant evidence of DNA repair was absent in primary hepatocytes from two human donors. At the same concentrations a modest but dose-related increase of micronucleated cells, that reached the level of statistical significance at 33 mg/l, was present in primary rat hepatocytes and in one of two human donors. In human lymphocytes exposed to subtoxic concentrations ranging from 0.78 to 12.5 mg/l a reproducible concentration dependent clastogenic effect was absent. In partially hepatectomized female rats treated with a single p.o. dose of 1000 mg/kg, the frequency of micronucleated cells was 5.2-fold higher than in controls in the liver, but only 2.0-fold higher in polychromatic erythrocytes of the bone marrow. In rats of the same sex given azoxymethane as initiator of colon carcinogenesis the oral administration for 8 successive weeks of 10 mg/kg omeprazole on alternate days increased the response to azoxymethane, as indicated by the occurrence in colon mucosa of a modest but statistically significant increase in both the average number and size of aberrant crypt foci. Taken as a whole, our results suggest that omeprazole behaves as a weak genotoxic agent for the rat liver. Reliable information about the potential genotoxic risk to humans requires further studies on primary cells from a wide number of donors.

Adult↗
PubMed2001

Whole almonds and almond fractions reduce aberrant crypt foci in a rat model of colon carcinogenesis.

Almonds and other nuts appear to confer health benefits despite their high fat content. To assess the effect of almonds on colon cancer, whole almond-, almond meal- or almond oil-containing diet effects on aberrant crypt foci (ACF) in azoxymethane-treated F344 male rats were investigated. Six-week-old male F344 rats were fed the various almond and control diets and given subcutaneous injections of azoxymethane (15 mg/kg body weight) twice 1 week apart. After 26 weeks animals were injected with bromodeoxyuridine 1 h prior to sacrifice, after which colons were evaluated for ACF and cell turnover (labeling index, LI). Whole almond ACF and LI were both significantly lower than wheat bran and cellulose diet groups (-30 and -40%, respectively), while almond meal and almond oil ACF and almond meal LI declines were only significant vs. cellulose (P<0.05). These results suggest that almond consumption may reduce colon cancer risk and does so via at least one almond lipid-associated component.

Animals↗
PubMed1998

Inhibitory effects of bovine lactoferrin on intestinal polyposis in the Apc(Min) mouse.

Chemopreventive effects of bovine lactoferrin (bLF), previously shown to strongly inhibit intestinal carcinogenesis in rats (K. Sekine, E. Watanabe, J. Nakamura, N. Takasuka, D.J. Kim, M. Asamoto, V. Krutovskikh, T.H. Baba, T. Ota, M.A. Moore, M. Masuda, H. Sugimoto, H. Nishino, T. Kakizoe, H. Tsuda, Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin administration in F344 rats, Jpn. J. Cancer Res. 88 (1997) 523-526; K. Sekine, Y. Ushida, T. Kuhara, M. Iigo, H. Baba-Toriyama, M.A. Moore, M. Murakoshi, Y. Satomi, H. Nishino, T. Kakizoe, H. Tsuda, Inhibition of initiation and early stage development of aberrant crypt foci and enhanced natural killer activity in male rats administered bovine lactoferrin concomitantly with azoxymethane, Cancer Lett. 121 (1997) 211-216), on spontaneous intestinal polyp development were assessed in the ApcMin mouse, a model for both familial adenomatous polyposis and sporadic colon cancers. In the experiment, 54 mice at 6 weeks of age were given 2% bLF (15 mice), 0.2% bLF (15 mice) and AIN-93G (24 mice) as basal diet ad libitum for 8 weeks. An overall tendency for a reduction in the total number of polyps in the small intestine was evident in the bLF-treated animals, along with significant suppression in the jejunum at the 2% dose (P < 0.05, 68% of the control). In addition, body growth suppression, presumed to be due to anemia and/or intussusception as a consequence of numerous polyps in the intestine, was alleviated. No toxic effects were observed in the intestinal epithelium. Although not as obvious as observed for the rat case, the data suggest that bLF may be a chemopreventor of intestinal polyposis.

Animals↗
PubMed1996

Butyrate enemas in experimental colitis and protection against large bowel cancer in a rat model.

BACKGROUND & AIMS: Butyrate is effective in experimental colitis by increasing transglutaminase activity. Because ulcerative colitis increases the risk of colonic neoplasia, the aim of this study was to investigate whether butyrate treatment reduces mucosal sensitivity to colon cancer development in rats with experimental colitis. METHODS: Colon cancer was induced by azoxymethane injections in 10 rats with trinitrobenzensulfonic acid-induced colitis and 10 rats without colitis. Three additional groups of rats with colitis were treated with butyrate, mesalamine, and saline enemas, respectively, twice daily for 8 weeks; 1 week after colitis induction, tumors were induced. Biopsy specimens for assessment of proliferation pattern and transglutaminase activity were obtained during the latent period of cancer development. Characteristics of tumors were recorded 27 weeks after the first exposure to azoxymethane. RESULTS: Experimental colitis enhanced carcinogenesis; butyrate therapy reduced both incidence and size of tumors and also affected colonic proliferation pattern. Transglutaminase levels were restored by butyrate treatment in rats with colitis. CONCLUSIONS: The protective effect of butyrate against large bowel cancer in experimental colitis suggests its usefulness in long-term therapy to decrease disease relapses and to reduce colon cancer risk in ulcerative colitis.

Animals↗
PubMed2006

Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia.

BACKGROUND & AIMS: The nonsteroidal anti-inflammatory drug-activated gene (NAG-1) was identified as a proapoptotic, antitumorigenic protein in vitro, induced by many antitumorigenic and chemopreventive drugs including cyclooxygenase inhibitors. However, its antitumorigenic activity has not been elucidated in vivo. METHODS: Transgenic mice were generated that ubiquitously overexpress human NAG-1 under the control of a chicken beta-actin promoter (CAG). The NAG-1 transgenic mice (NAG-(Tg+)) were characterized, and then the antitumorigenic activity was evaluated with 2 colorectal carcinogenesis models: chemical induction with azoxymethane and genetic induction using the Apc(Min+) mutation. RESULTS: NAG-(Tg+) showed no apparent phenotype other than a reduction in body weight, particularly in males. To examine whether NAG-1 expression would suppress intestinal tumorigenesis, the NAG-(Tg+) mice were treated with the colorectal carcinogen azoxymethane. NAG-(Tg+) mice developed 50% fewer aberrant crypt foci and no tumors, in comparison with nontransgenic littermates. This result demonstrates that expression of this human protein in vivo can suppress chemically induced carcinogenesis in the colon. The NAG-(Tg+) mice were also crossed with Apc(Min+) mice to determine the effect of the transgene on intestinal polyp formation. NAG-(Tg+) mice heterozygous for the Apc(Min+) mutation had a significantly reduced polyp load (60%) compared with nontransgenic Apc(Min+) littermates. CONCLUSIONS: Our results support NAG-1 as an important regulator of intestinal adenoma growth in vivo and suggest that NAG-1 may act as a tumor suppressor gene.

Animals↗
PubMed1995

Effects of dietary restriction and fasting on selected rat liver enzymes of xenobiotic metabolism and on AOM-induced DNA guanine methylation in rat liver and colon.

Using five- to eight-week-old male F344 rats and a high-fat (23.5% corn oil) modified AIN-76A diet, we examined the effects of dietary restriction (a 3-wk 30% reduction of food intake with respect to ad libitum-fed controls) or complete fasting (2 days without food) on the activities of hepatic xenobiotic metabolizing enzymes in vitro and on azoxymethane- (AOM) induced formation of O6-methylguanine and 7-methylguanine in liver and colon DNA in vivo. Compared with ad libitum-fed rats, fasting increased total liver cytochrome P450 by 32%, microsomal aniline hydroxylase by 270%, N-nitrosodimethylamine demethylase by 270%, and azoxymethane hydroxylase by 320%. Liver benzo[a]pyrene (BP) hydroxylase and glutathione-S-transferase were decreased by 39% and 21%, respectively, whereas NADPH cytochrome c reductase and UDP glucuronyltransferase were unchanged. DNA methylation in the livers of fasted animals was 20-31% greater six hours after a 15 mg/kg sc injection of AOM than in ad libitum-fed controls, whereas DNA methylation in the colon was slightly lower. In three-week diet-restricted animals. there were small but not statistically significant changes in the various enzyme activities and in AOM-induced DNA methylation compared with the ad libitum-fed controls, with the exception of BP hydroxylase, which showed a 26% decrease. However, the trends in the increase or decrease of each parameter, although small in magnitude, were similar to those observed in the case of fasting, suggesting that the effects might become significant if the duration of diet restriction were prolonged. The enhancement of AOM metabolism in rat liver by fasting, leading to increased liver DNA methylation, is different from that produced by chemical inducers, such as ethanol, where no increase in liver DNA methylation is observed.

Aniline Hydroxylase↗
PubMed2002

Altered expression of c-myc, p16 and p27 in rat colon tumors and its reversal by short-term treatment with chemopreventive agents.

Modulation of gene expression in tumors has the potential of being a surrogate end-point biomarker for chemoprevention. Thus, we determined the modulation by chemopreventive agents of the protein and mRNA expression of genes in rat colon tumors. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane. Forty-seven weeks later, they received aspirin (600), calcium chloride (50 000), 2-(carboxyphenyl) retinamide (2-CPR, 315), alpha-difluoromethylornithine (DFMO, 3000), piroxicam (200), quercetin (33 600), 9-cis retinoic acid (9-cis RA, 30), rutin (3000), or sulindac (280) in their diet at the indicated mg/kg concentration for 7 days and were then killed. In colon tumors relative to the mucosa, the protein and mRNA levels of c-myc were increased, while the levels of p16 and p27 were decreased. Calcium chloride, DFMO, piroxicam and sulindac administered for 7 days decreased the mitotic index and reduced the protein and mRNA levels of c-myc in colon tumors. Calcium chloride, DFMO and piroxicam increased the protein and mRNA levels of p16 and along with sulindac increased the protein level of p27, but not its mRNA. The other agents failed to modulate both the mitotic index and the expression of the genes. The ability of the chemopreventive agents to prevent colon tumors was determined. Male F344 rats were administered three weekly injections of 15 mg/kg azoxymethane and 8 weeks later they were administered aspirin, 2-CPR, DFMO, piroxicam, 9-cis RA and rutin in their diet. The rats were killed 26 weeks after they started to receive the chemopreventive agents. The multiplicity of colon tumors was reduced by DFMO and piroxicam, increased by rutin and not affected by the other agents. Hence, agents that prevented colon cancer decreased the mitotic index and altered the expression of c-myc, p16 and p27 suggesting that modulation in the expression of these genes are potential biomarkers for chemopreventive activity.

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