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PubMed2001

Effects of indole-3-carbinol on immune responses, aberrant crypt foci, and colonic crypt cell proliferation in rats.

Male Sprague-Dawley rats were treated orally with indole-3-carbinol (13C) for 7 wk at levels of 150, 100, and 50 mg/kg body weight. The rats were injected with 10 mg/kg body weight of the colon carcinogen, azoxymethane (AOM) on d 2 and 9 of 13C treatment. At termination of the study, all rats were assessed for immune function (humoral immunity, specific cell-mediated immunity, and nonspecific cell-mediated immunity). Colonic tissue was collected and examined for the presence of aberrant crypt foci (ACF) and proliferation of crypt cells. Antibody responses to antigen challenge were significantly suppressed in the animals exposed to the high dose of 13C. Delayed-type hypersensitivity responses, natural killer cell activity, the number and multiplicity of ACF, and cell proliferation parameters were not significantly different from those of the controls. Therefore, there was no clear protective or enhancing effect of 13C on ACF numbers or colonic cell proliferation indices. There was no strong correlation between changes in immune responses and the preneoplastic biomarkers of colon cancer.

Animals↗
PubMed2004

Interaction of conjugated linoleic acid, sphingomyelin, and butyrate on formation of colonic aberrant crypt foci and immune functions in rats.

This study was designed to investigate possible additive or synergistic action among sphingomyelin (SPH), cis-9,trans-11-conjugated linoleic acid (CLA), and butyrate (BTY) against colon cancer and modulation of immune functions in vivo in male Sprague-Dawley rats. Each of the 5 groups of rats was fed either 35 mg SPH, 100 mg CLA, or 100 mg BTY/kg body weight, a combination of the 3 compounds at the same doses, or none of the compounds, for 7 wk. Rats were injected with azoxymethane, a colon carcinogen, to induce the formation of aberrant crypt foci, preneoplastic lesions of colon cancer. Parameters measured included number and multiplicity (number of crypts per focus) of aberrant crypts, immune functions such as innate immunity (natural killer cell cytotoxicity), humoral immunity (development of antibodies), and cell-mediated immunity (delayed-type hypersensitivity). Results show that the groups treated with SPH, CLA, and BTY individually had significantly higher natural killer cell (NK) cytotoxicity than the group treated with all compounds. The CLA group also had significantly higher NK activity than the control group. This study shows that the three compounds may not act additively or synergistically either to inhibit the development of aberrant crypts or to enhance immune functions. In fact, exposure to the combined compounds may be antagonistic to enhancement of NK function by the individual chemicals.

Animals↗
PubMed1990

Inhibition of experimental colorectal carcinogenesis by dietary N-6 polyunsaturated fats.

The influence of dietary fats on azoxymethane-induced colorectal carcinogenesis and erythrocyte, adipose, colon mucosa and tumour tissue fatty acids was investigated in 228 Wistar rats. The two main diets compared were beef suet rich in saturated fatty acids and corn oil rich in a linoleic acid, an N-6 polyunsaturated fatty acid. The animals were placed in one of four dietary groups: A = 5% saturated fat, B = 20% saturated fat, C = 5% N-6 fat and D = 20% N-6 fat. There was no difference in the number of adenomas between any of the dietary groups. The mean (+/- SEM) carcinoma yield per rat was A = 0.93 +/- 0.28, B = 1.93 +/- 0.50, C = 0.70 +/- 0.07, D = 0.13 +/- 0.04; the tumour yields in rats fed the saturated fat diets were significantly different from each other and from those fed the N-6 fat diets. The fatty acid profiles in all tissues were dependent upon the type and level of dietary fat and the tissue type. Arachidonate was higher in tumours compared to normal mucosa. Significant correlations were found between adipose linoleate (reflecting dietary intake) and tumour oleate and tumour arachidonate but not with the colorectal mucosa of control animals. This is the first in vivo study to show reduced colorectal carcinogenesis by N-6 polyunsaturated fatty acids.

Adenoma↗
PubMed1990

Dose-dependent inhibition of large intestinal cancer by inositol hexaphosphate in F344 rats.

We have previously reported that inositol hexaphosphate (InsP6) inhibits mitosis and large intestinal cancer (LIC) in F344 rats and CD1 mice when given as 1 or 2% solution in drinking water at the unadjusted pH of 11.3. The purpose of this study was to determine whether InsP6 (i) shows a dose-response inhibition of LIC, and (ii) retains its anti-neoplastic effect at physiological pH. Since InsP6 is known to be a chelator of divalent cations, in preparation for putative clinical trials in humans, we also looked at the mineral bioavailability. F344 rats were fed 0.1% (pH 10.8), 1% (pH 11.3) and 1% (pH 7.4) Na-InsP6 in drinking water. Two weeks following the beginning of InsP6 supplementation, rats were given six injections of azoxymethane (AOM) at a dose of 8 mg/kg body wt/week and were killed 30 weeks following the last injection. Compared to the untreated control rats injected with AOM, 1% InsP6 (pH 11.3) reduces tumor prevalence by 52.2% (P less than 0.01), tumor frequency by 55.8% (P = 0.001) and tumor size by 62.3% (P = 0.001); 0.1% InsP6 showed a lesser reduction in tumor prevalence (21%) but a greater reduction in tumor size 71% (P = 0.001). While there was no significant difference in tumor prevalence and frequency between the two pH groups, the tumor size following 1% InsP6 (pH 7.4) was the smallest (65% smaller than those of pH 11.3, P less than 0.005). There was no significant difference in the serum Mg2+, Ca2+, Fe2+ and Zn2+ level between control rats and those treated with 1% InsP6. We therefore demonstrate that InsP6 (i) is consistently anti-neoplastic for LIC in a dose-dependent manner, (ii) retains its anti-neoplastic activity at physiological pH and (iii) has no demonstrable toxic effect on long-term administration as evident by body wt data and serum mineral levels.

Animals↗
PubMed1992

The effect of high-risk and low-risk diets on aberrant crypt and colonic tumor formation in Fischer-344 rats.

Eighty Fischer-344 male rats were divided into eight groups. Half the groups were given a high-risk diet (HRD) that was high in fat, low in fiber and low in calcium, while the remaining groups were given a low-risk diet (LRD) that was low in fat, high in fiber and high in calcium. After 4 weeks, four groups were then given two weekly s.c. injections of azoxymethane (AOM) (15 mg/kg body wt), and four groups were given saline injections. At the end of 6 weeks the rats were either continued on HRD, LRD, or crossed over from HRD to LRD, or LRD to HRD for an additional 6 weeks. The rats were then killed and the influence of different dietary regimens on the induction of foci of aberrant crypts (AC) in their colons was compared. The number of foci of AC was highest in the AOM-injected HRD/HRD dietary group (8.83 +/- 0.98), followed by the AOM-injected LRD/HRD group (5.37 +/- 0.75), the HRD/LRD group (3.32 +/- 0.36) and the LRD/LRD group (2.93 +/- 0.32). Except for the HRD/HRD control group, which developed a small but significant number of foci of AC (1.24 +/- 0.19), the other saline-injected dietary groups showed no significant numbers of foci of AC. Two groups of rats on HRD/HRD (AOM and saline-injected), and two groups of rats on HRD/LRD (AOM and saline-injected) were continued on HRD and LRD respectively for an additional 14 weeks. A continuous HRD in AOM-injected rats induced colon tumors in 92% of rats, while the crossover from HRD to LRD suppressed the tumor incidence to 33%. Neither diet induced any tumors in saline-injected rats. The results clearly show that the influence of HRD and LRD on the induction of foci of AC and their distribution in the colon, correlated with the induction and distribution of tumors in the colon.

Animals↗
PubMed1992

Inhibition of colon carcinogenesis by prostaglandin synthesis inhibitors and related compounds.

The inhibitory effect of 40 and 80% maximum tolerated dose (MTD) levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid on colon carcinogenesis was investigated in male F344 rats. The MTD levels of piroxicam, ibuprofen, ketoprofen and glycyrrhetinic acid as determined in male F344 rats were 500, 500, 250 and 3000 p.p.m. respectively. At 5 weeks of age, groups of male F344 rats were fed the control (AIN-76A) diet and 40 and 80% MTD levels of each test agent in AIN-76A diet. At 7 weeks of age, all animals except the vehicle (saline)-treated controls received azoxymethane (AOM) at a dose rate of 15 mg/kg body wt, once weekly for 2 weeks. All animals were necropsied 50 weeks after the second AOM injection and colon tumor incidences were compared among the groups fed the control diet and chemopreventive agents. Animals fed 400 (80% MTD) and 200 p.p.m. (40% MTD) of piroxicam, 400 p.p.m. (80% MTD) of ibuprofen and 200 p.p.m. (80% MTD) of ketoprofen showed a significant inhibition of colon tumorigenesis as compared to those fed the control diet. Results analyzed by the linear regression method suggested a dose-dependent inhibition of colon carcinogenesis with increasing levels of piroxicam or ibuprofen. In contrast, glycyrrhetinic acid had no measurable chemopreventive effect on colon carcinogenesis.

Animals↗
PubMed1993

Initiation and promotion of colonic aberrant crypt foci in rats by 5-hydroxymethyl-2-furaldehyde in thermolyzed sucrose.

We have previously shown that thermolyzed sucrose in the diet promotes the growth of aberrant crypt foci (ACF) in the rat. HPLC analysis of the light caramel colored product showed that it contained 1% 5-hydroxymethyl-2-furaldehyde (HMF), confirmed by mass and NMR spectroscopy. To determine whether HMF was responsible for the promotion of ACF by thermolyzed sucrose, 45 F344 female rats were initiated with the colon carcinogen azoxymethane (AOM), and a week later were randomized to four groups receiving AIN-76 diets containing untreated sucrose, 20% thermolyzed sucrose, 20% butanol extracted thermolyzed sucrose (HMF free) or 1% HMF. Thermolyzed sucrose in the diet led to larger ACF as previously observed. Thermolyzed sucrose extracted to remove HMF, did not affect ACF size, but 1% HMF added to the diet led to a larger ACF both with relation to average size and number of ACF of larger sizes (P < 0.05). To determine whether HMF had initiating effects, 172 female F344 rats were given water, HMF (at doses to 300 mg/kg) or AOM (5 mg/kg) by gavage twice and the total number of ACF was scored 30 days later. The results demonstrated that HMF induces ACF in a dose-dependent manner (P < 0.02), though the effect was much weaker than that of AOM. We conclude that sugar heated under household cooking conditions may act as both an initiator and a promoter of colon cancer because of the presence of HMF.

Animals↗
PubMed1993

Sucrose enhancement of the early steps of colon carcinogenesis in mice.

The association of refined sugars and colorectal cancers and polyps in three recent case-control studies led us to investigate the effects of sucrose, fructose and glucose on colonic epithelial proliferation and sensitivity to carcinogenesis. CF1 and C57BL/6J mice were used; proliferation was assessed as vincristine-accumulated mitotic figures per crypt section; sensitivity to carcinogenesis was assessed as the number of aberrant crypt foci (ACF) per colon observed following the colon carcinogen, azoxymethane (AOM, 3 mg/kg and 5 mg/kg). Oral gavages of sucrose and fructose in CF1 mice (10 g/kg) increased colonic proliferation 16 h later (2.8 +/- 0.6 and 4.1 +/- 0.7 (mean +/- SEM) accumulated mitotic figures/crypt section), compared with glucose and water (1.0 +/- 0.2 and 0.4 +/- 0.1). Sucrose and fructose given 14 h prior to the AOM (5 mg/kg) increased the sensitivity of the colon to carcinogenesis (18.4 +/- 1.5 and 13.1 +/- 1.8 ACF/colon), compared with glucose and water (11.4 +/- 2.0 and 8.6 +/- 1.1). Similar results were observed with C57BL/6J mice. We conclude that dietary sucrose and fructose may represent risk factors for colorectal cancer through a direct effect of the sugars on colonic epithelial proliferation.

Animals↗
PubMed1995

Chemopreventive effects of calcium but not aspirin supplementation in cholic acid-promoted colon carcinogenesis: correlation with intermediate endpoints.

Epidemiological studies have suggested that increased intake of calcium (Ca) or aspirin (ASA) is associated with a reduced risk for colon cancer. To delineate a possible mechanism of action, the present study used male F344 rats in an azoxymethane (AOM)-induced colon tumor model to study the single and interactive effects of Ca and ASA on cholic acid-promoted experimental colon carcinogenesis. Following initiation with AOM, a promotion diet containing 0.5% cholic acid was fed for 34 weeks until the adenoma development stage. Cholic acid was used as a surrogate for high-fat diets and to promote carcinogenesis. Diets were supplemented with CaCO3 (2% Ca by weight), 250 p.p.m. ASA, or both. After 34 weeks, the diets were switched during the progression stage and rats were killed at week 51. Several intermediate endpoints were examined during the course of AOM carcinogenesis to determine their reliability as predictors of colon cancer risk. Intermediate endpoints included colon crypt height measurement, colon mucosal ornithine decarboxylase (ODC) and colon mucosal protein kinase C (PKC) activities. The biomarkers were examined at the beginning of the study at 2 weeks, and thereafter at 5, 15, 30 and 40 weeks of dietary treatment. Animals were necropsied at week 51 and tumor incidence and numbers were analyzed for correlation with biomarkers. Survival was highest in the group fed CaCO3 during the promotion stage and tumor burden was lowest in groups fed CaCO3 during this stage. Supplementation during the progression stage was ineffective. The cholic acid promotion model resulted in increased ODC which was inhibited by intervention during the promotion stage with Ca, but not ASA. PKC was also activated by cholic acid feeding, and this effect was modulated by intervention in the promotional stage with Ca or ASA. Colon tumor incidence and burden was increased by cholic acid promotion and decreased by Ca, but not affected by ASA. In summary, Ca is a more effective chemopreventive agent in cholic acid-promoted colon carcinogenesis than ASA, impacting both incidence and tumor number. Colonic ODC, but not PKC may be a suitable predictor of risk and response in chemoprevention trials for colon cancer.

Animals↗
PubMed1996

Dietary fat and fiber differentially alter intracellular second messengers during tumor development in rat colon.

The effect of fat, fiber and carcinogen on colonic epithelial intracellular second messengers 1,2-diacyl-sn-glycerol (DAG), ceramide, and the steady-state level of phospholipase C (PLC-gamma1) was determined in 160 male Sprague-Dawley rats (10 rats per group). The study was a 2 x 2 x 2 x 2 factorial design with two types of fat (corn oil or fish oil), two types of fiber (cellulose or pectin), two injected subgroups (with or without azoxymethane (AOM), and two time points (15 and 37 weeks). At the final time point (37 weeks) there were an additional 20 rats per diet in each of the carcinogen-treated groups for tumor analyses only (n = 80), for a total of 240 animals in the entire study. At each time point (15 and 37 weeks), 80 rats were killed and colonic mucosa obtained for DAG, ceramide and PLC-gamma1 assays. At the first time point (15 weeks), there was no microscopic evidence of tumors. At the final time point (37 weeks), fish oil resulted in a lower proportion of animals with adenocarcinomas relative to corn oil feeding (56.1 % versus 69.6 %, P < 0.05). There was no significant main effect of fiber on the percentage of animals with tumors. At 15 weeks post-injection, AOM injected animals fed corn oil-containing diets had a significantly (P < 0.001) higher DAG mass and steady-state levels of PLC-gamma1 compared with AOM-injected animals fed fish oil and saline injected rats on all diets. Animals fed corn oil diets also had a significantly (P < 0.01) elevated mucosal ceramide mass compared with fish oil fed animals. Moreover, rats injected with AOM had a significantly (P < 0.02) elevated colonic mucosal DAG/ceramide ratio versus saline injected animals. In contrast, dietary fiber had no effect on any of the parameters measured at 15 weeks. However, at 37 weeks post-injection, dietary fiber significantly altered DAG (P < 0.02), and PLC-gamma1 expression (P < 0.05) in the absence of an effect on tumor incidence. These data demonstrate that the ability of dietary fish oil to reduce experimental colon carcinogenesis may be mediated by changes in colonic intracellular mediators during the initial stages of tumorigenesis.

Adenocarcinoma↗
PubMed1996

Growth features of aberrant crypt foci that resist modulation by cholic acid.

Previously, we demonstrated that feeding rats a diet containing 0.2% cholic acid (CHA-diet) resulted in the elimination or remodelling of a number of aberrant crypt foci (ACF) in their primal stages (1-3 crypts/focus). The present investigation was conducted to determine if ACF with advanced growth features will respond differently than their primal counterparts to the CHA-diet. Sprague-Dawley male rats were injected with azoxymethane (20 mg/ kg) and were maintained on a control diet for 21 weeks. At week 21, three rats were killed and their colons were assessed for ACE. The remaining animals were randomly divided into two groups, which were fed a control diet or a CHA-diet respectively, After 3 weeks of feeding, the rats (n = 5) were killed and their colons were assessed for the number, size (area occupied by each focus) and crypt multiplicity (number of crypts/focus). The CHA-diet resulted in a significant (P </= 0.05) reduction in the number of ACF with 1-2 crypt multiplicity. When compared to the control group, the CHA group ACF with 1-2 crypts/focus were reduced by 70%; with 3-4 crypts/focus, a 48% reduction; and with >4 crypts/focus, a 50.4% reduction. Treatment with CHA resulted in a marked reduction in the population of ACF with 1-2 or 3-4 crypt multiplicity with area >5-1Ox10(-2) mm2. These findings demonstrate that ACF with advanced growth features are phenotypically different from their primal counterparts in resisting the responses elicited by the CHA-diet even at a late time point, and that morphological heterogeneity among ACF may represent different biological states.

Analysis of Variance↗
PubMed1997

Citrus auraptene inhibits chemically induced colonic aberrant crypt foci in male F344 rats.

The modifying effect of dietary administration of auraptene isolated from the peel of citrus fruit (Citrus natsudaidai Hayata) 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 ACF. They also received diets containing 100 or 500 p.p.m. auraptene for 5 weeks, starting 1 week before the first dose of AOM. At termination of the study (week 5) dietary administration of auraptene caused a significant reduction in the frequency of ACF in a dose-dependent manner (P < 0.05). Feeding of auraptene suppressed expression of cell proliferation biomarkers (5-bromo-2'-deoxyuridine labeling-index, ornithine decarboxylase activity, polyamine content and number of silver stained nucleolar organizer region protein particles) in the colonic mucosa and the occurrence of micronuclei caused by AOM. Also, auraptene increased the activities of phase II enzymes (glutathione S-transferase and quinone reductase) in the liver and colon. These findings might suggest that inhibition of AOM-induced ACF may be associated, in part, with increased activity of phase II enzymes in the liver and colon and suppression of cell proliferation in the colonic mucosa.

Animals↗
PubMed1997

AOM-induced mouse colon tumors do not express full-length APC protein.

While evidence in both sporadic and inherited human colorectal cancer and MIN mice implicate the tumor suppressor gene, APC, in the causation of colorectal carcinogenesis, this gene has not been confirmed to be involved in rodent chemically-induced colon cancer models (RCCM). These experimental models are widely used to elucidate mechanisms involved in colon carcinogenesis (initiation, promotion and progression) as well as studies on chemoprevention (dietary and other) and intervention. To validate the RCCM as relevant models for sporadic human colorectal cancer, and to facilitate research on the role of the APC gene in colon carcinogenesis, we investigated the role of APC in azoxymethane (AOM)-induced colorectal tumors in mice. Using an antibody that recognizes the carboxy terminus of APC, we have characterized the pattern of staining observed in normal mouse intestinal tissue, in MIN mouse intestinal adenomas and in AOM-induced mouse colon tumors. The APC protein was localized in the cytoplasm of normal colonic epithelial cells. In the small intestine there was APC immunoreactivity along the villous and staining of the Paneth cells at the base of the glands. In the proximal and distal colonic crypts there appeared to be a gradient of staining which increased towards the luminal surface. This gradient was not as apparent in the small intestinal villi. Nuclei and mucus in the goblet cells showed no immunoreactivity. MIN mouse small bowel and colonic adenomas, known to have lost APC, stained negatively for APC. AOM-induced adenomas and carcinomas also consistently stained negatively using this antibody. This study demonstrates for the first time the loss of wild-type APC protein in AOM-induced mouse colon tumors and suggests that alterations in expression of this tumor suppressor gene, which is so commonly mutated in human colon cancer, is also involved in this animal model of colon cancer.

Adenoma↗
PubMed1997

Dietary fish oil blocks carcinogen-induced down-regulation of colonic protein kinase C isozymes.

In order to elucidate the influence of dietary constituents on colonic intracellular signal transduction, the effect of different fats on rat colonic epithelial protein kinase C (PKC) alpha (classical), delta (novel) and lambda-zeta (atypical) expression was determined in carcinogen-treated animals. Sprague-Dawley rats were provided with one of two fats (corn oil and fish oil); plus or minus the carcinogen azoxymethane (AOM) and killed at two time points (15 and 37 weeks) in a 2x2x2 factorial design. At 5 and 6 weeks of age, animals were injected s.c. with either AOM at a dose of 15 mg/kg body weight or saline once a week for 2 weeks and continued on the same diet until termination of the study. At 15 and 37 weeks after the second injection, 10 rats from each treatment group were killed. Colonic PKC alpha, delta and lambda-zeta steady-state protein and mRNA levels were determined using immunoblotting and relative quantitative polymerase chain reaction, respectively. Colonic mucosa from rats injected with AOM had significantly suppressed membrane and cytosolic PKC alpha and cytosolic lambda-zeta protein levels (P < 0.05) as compared to saline-injected control animals at both time points. In contrast, rats fed fish oil diets had significantly higher (P < 0.05) cytosolic PKC delta and lambda-zeta protein levels relative to animals fed corn oil diets. However, the effect of diet and AOM on the steady-state expression of PKC alpha, delta and zeta mRNA was not consistent with changes in the respective isozyme protein levels, suggesting regulation at the post-transcriptional level. These data demonstrate that dietary fish oil blocks the carcinogen-induced decrease in the steady-state levels of colonic mucosal PKC delta and lambda-zeta, which may in part explain why this fat source protects against colon cancer development.

Animals↗
PubMed1998

Effect of Bifidobacterium longum and inulin on gut bacterial metabolism and carcinogen-induced aberrant crypt foci in rats.

The effect of Bifidobacterium longum (4 x 10(8) viable cells/g diet) and a derivative of inulin ('Raftiline HP'; 5% w/w in diet) on colonic aberrant crypt foci (ACF) induced by the colon carcinogen azoxymethane (AOM) has been studied. The concentration of ammonia, a putative tumour promoter produced by bacterial degradation of protein and urea, and the activities of certain bacterial enzymes thought to play a role in colon carcinogenesis, beta-glucuronidase and beta-glucosidase were also assayed. Consumption of either B. longum or inulin was associated with a decrease (26 and 41%, respectively) in AOM-induced small ACF (i.e. those comprising 1-3 aberrant crypts per focus). Combined administration of the bifidobacterium and inulin resulted in more potent inhibition of ACF than administration of the two separately, achieving 80% inhibition of small ACF. Furthermore, the combined administration significantly decreased the incidence (by 59%) of large ACF (>4 aberrant crypts per focus), which are considered to be predictive of eventual tumour incidence. Since the dietary treatments were started 1 week after the carcinogen dose, the results suggest that B. longum and inulin may be affecting the early promotion phase of the carcinogenic process. Consumption of diets containing B. longum, inulin or both were also associated with decreases in beta-glucuronidase activity and ammonia concentration in the caecal contents. Both these factors have been associated with carcinogenesis of the colon in experimental animal models. In rats given inulin-containing diets (with or without B. longum) an increase in caecal wt and beta-glucosidase activity and a decrease in caecal pH were observed. The results suggest that consumption of B. longum or inulin was associated with potentially beneficial changes in caecal physiology and bacterial metabolic activity in relation to tumour risk and in the incidence of putative preneoplastic lesions in the colon. The results also indicated that combined treatment with the two agents was more effective in reducing colonic lesions.

Ammonia↗
PubMed1998

Chemopreventive effect of squalene on colon cancer.

Epidemiologic and laboratory studies suggest a cancer protective effect and/or lack of a tumor promoting effect by dietary olive oil as compared with other types of non-marine oils. Squalene, a constituent of olive oil, and a key intermediate in cholesterol synthesis may be regarded as partially responsible for the beneficial effects of olive oil, which include decreased mortality rates among populations with high olive oil consumption. Thus, in this study we have assessed the chemopreventive efficacy of squalene on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). In addition, we measured the effect of squalene on serum cholesterol levels in the rats. Male F34 rats (5 weeks old) were fed the control diet (modified AIN-76A) or experimental diets containing 1% squalene or 320 p.p.m. sulindac. Two weeks later, all animals except those in vehicle (normal saline)-treated groups were s.c. injected with AOM (15 mg/kg body wt, once weekly for 2 weeks). At 16 weeks of age, all rats were killed, colons were evaluated for ACF and serum was assayed for the cholesterol levels. As expected, dietary administration of sulindac suppressed ACF development and reduced crypt multiplicity, i.e. number of aberrant crypts/focus. Administration of dietary squalene inhibited total ACF induction and crypt multiplicity by approximately >46% (P < 0.001). Further, squalene at a level of 1% did not show any significant effect on serum cholesterol levels. Our finding that squalene significantly suppresses colonic ACF formation and crypt multiplicity strengthens the hypothesis that squalene possesses chemopreventive activity against colon carcinogenesis.

Animals↗
PubMed1998

Nuclear translocation of beta-catenin in hereditary and carcinogen-induced intestinal adenomas.

The physical interaction between beta-catenin and the adenomatous polyposis coli (APC) gene, and the ability of APC to regulate cytoplasmic levels of beta-catenin suggest a role for beta-catenin in colorectal carcinogenesis. In this study, we found that beta-catenin immunoreactivity was detected exclusively in the cell membrane and cytoplasm of morphologically normal intestinal epithelial cells with predominant distribution in the differentiated nonproliferative cell population. In contrast, beta-catenin was localized predominantly in the nucleus of adenomas from Min/+ mice and transgenic mice expressing a mutant truncated form of the APC gene (Apc(delta716) mice). Beta-catenin was expressed predominantly at the cell membrane and cytoplasm of the nontransformed rat intestinal epithelial (RIE-1) cells in culture, whereas predominantly nuclear localization of beta-catenin was observed in the human colon cancer cell line SW480. In the azoxymethane (AOM) treated rats, overexpression and nuclear localization of beta-catenin was observed in all adenomas. Previous studies have indicated the incidence of APC mutations amongst AOM-induced tumors to be 15% or less. These results demonstrate that nuclear localization of beta-catenin is a common event in colorectal tumorigenesis.

Adenoma↗
PubMed1999

Effect of retinoids on AOM-induced colon cancer in rats: modulation of cell proliferation, apoptosis and aberrant crypt foci.

We have previously reported that the retinoids, 4-(hydroxyphenyl)retinamide (4-HPR) and 9-cis-retinoic acid (RA) prevented azoxymethane (AOM)-induced colon tumors and along with 2-(carboxyphenyl)retinamide (2-CPR) prevented aberrant crypt foci (ACF). In this study, we evaluated the effect of 2-CPR on AOM-induced colon tumors and the effect of the three retinoids on apoptosis and cell proliferation. Male F344 rats were administrated 15 mg/kg AOM at weeks 7 and 8 of age. 2-CPR (315 mg/kg) was administered in the diet starting either 1 week before or at week 12 after the first dose of AOM. The rats continued to receive the 2-CPR until killed at week 46. Unlike the demonstrated prevention of colon cancer by the other two retinoids, both dosing schedules of 2-CPR resulted in an approximate doubling of the yield of colon tumors. In adenomas, 2-CPR, 4-HPR and 9-cis-RA were equally effective in reducing mitotic activity, while only 4-HPR and 9-cis-RA but not 2-CPR enhanced apoptosis. When administered for only the 6 days prior to killing 4-HPR but not 2-CPR decreased the Mitotic Index and increased the Apoptotic Index in adenomas. In non-involved crypts, chronic exposure to 4-HPR and 9-cis-RA in contrast to 2-CPR reduced the Mitotic Index and enhanced the Apoptotic Index. In concurrence with our previous study, both 2-CPR and 4-HPR were very potent in preventing ACF when administered in the diet starting 1 week before the first dose of AOM and continuing for the 5 weeks of the study. Hence, unlike the other two retinoids, 2-CPR, although very potent in preventing ACF, enhanced rather than prevented AOM-induced colon cancer. Furthermore, our results suggest that the effect of 2-CPR on tumor yield is different from 4-HPR and 9-cis-RA because, unlike them, it does not enhance apoptosis.

Adenocarcinoma↗