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PubMed2006

Predominant T helper type 2-inflammatory responses promote murine colon cancers.

Colon cancer is one of the most serious complications of inflammatory bowel diseases, especially ulcerative colitis (UC). Previous studies have shown that characteristic immunological event during inflammation in UC is the expression of T helper-type 2 (Th2) cell-derived cytokines. In this study, we investigated the influence of a predominant Th2-type cytokine response in colitis on carcinogen-induced colon tumors. Wild type (WT), interferon gamma (IFN-gamma) gene deficient (-/-) [Th2 dominant] or interleukin (IL)-4(-/-) [Th1-dominant] mice of BALB/c background were used in this study. To compare tumor formation, mice were given the carcinogen azoxymethane (AOM) and intrarectal administration of trinitrobenzene sulfonic acid (TNBS), to induce colitis. Thirty-three weeks after initial treatment, the total colon was examined. When IFN-gamma(-/-) mice were treated with AOM and TNBS, significantly higher number of tumors were seen (8.4 +/- 1.7) than in WT (3.3 +/- 2.9) or IL-4(-/-) (3.1 +/- 3.4) mice, which received identical treatments. A separate set of experiment, using less doses of AOM and TNBS also showed the higher frequency of tumor formation in IFN-gamma(-/-) mice than in IL-4(-/-) mice. Histologically, the tumors were well- or moderately-differentiated adenocarcinomas. No invasion into the submucosal or serosal layers of the intestine was seen. In immunohistological staining, some tumors in IFN-gamma(-/-) mice showed distinct nuclear expression of beta-catenin, in contrast to the strong membrane staining seen in tumors of IL-4(-/-) mice. In conclusion, colonic inflammation associated with Th2-dominant cytokine responses enhanced the formation of malignant neoplasms.

Adenocarcinoma↗
PubMed2006

Dietary administration with prenyloxycoumarins, auraptene and collinin, inhibits colitis-related colon carcinogenesis in mice.

We previously reported the chemopreventive ability of a prenyloxycoumarin auraptene in chemically induced carcinogenesis in digestive tract, liver and urinary bladder of rodents. The current study was designed to determine whether dietary feeding of auraptene and its related prenyloxycoumarin collinin can inhibit colitis-related mouse colon carcinogenesis. The experimental diets, containing the compounds at 2 dose levels (0.01 and 0.05%), were fed for 17 weeks to male CD-1 (ICR) mice that were initiated with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg body weight) and promoted by 1% (w/v) DSS in drinking water for 7 days. Their tumor inhibitory effects were assessed at week 20 by counting the incidence and multiplicity of colonic neoplasms and the immunohistochemical expression of proliferating cell nuclear antigen (PCNA)-labeling index, apoptotic index, cyclooxygenase (COX)-2, inducible nitric oxide (iNOS) and nitrotyrosine in colonic epithelial malignancy. Feeding with auraptene or collinin, at both doses, significantly inhibited the occurrence of colonic adenocarcinoma. In addition, feeding with auraptene or collinin significantly lowered the positive rates of PCNA, COX-2, iNOS and nitrotyrosine in adenocarcinomas, while the treatment increased the apoptotic index in colonic malignancies. Our findings may suggest that certain prenyloxycoumarins, such as auraptene and collinin, could serve as an effective agent against colitis-related colon cancer development in rodents.

Animals↗
PubMed1988

Inhibition by tetragastrin of experimental carcinogenesis in rat colon: effect of wheat bran consumption.

The effect of dietary wheat bran consumption on the anticarcinogenic action of tetragastrin upon colon carcinogenesis induced by azoxymethane was investigated in 122 inbred Wistar rats. Rats were given a control fiber-free diet or the same basal diet plus 20% wheat bran. From week 5, they were given 250 micrograms per kg body weight of tetragastrin in depot form every other day until the end of the experiment at week 45. Prolonged administration of tetragastrin resulted in a significant reduction of the incidence and number of colonic tumors per rat in the group given the fiber-free diet. The adenocarcinomas that did develop in this group had high mucin-producing activity, unlike the cancers produced in controls without tetragastrin. However, administration of tetragastrin had little or no influence on the incidence, number or histology of colonic tumors in the group given basal diet plus wheat bran. Dietary supplementation with wheat bran alone had little or no effect on the development or histology of colonic tumors. Before and during the administration of carcinogens, addition of fiber to the diet resulted in a significant fall in the colonic pH and a significant increase in the crypt column length, but administration of tetragastrin did not have an additive effect on the crypt column length in rats fed diet supplemented with fiber.

Adenocarcinoma↗
PubMed1992

Growth kinetics and chemoprevention of aberrant crypts in the rat colon.

Single and multiple colonic crypts exhibiting dysplasia that are detectable in situ by staining of rat colon with methylene blue are called aberrant crypts (AC) and may serve as an intermediate marker for colon cancer. In a characterization study, we have established the kinetics of AC growth and development over a period of 20 d following injection of rats with the carcinogen azoxymethane (AOM). AC are not present at 5 d post-injection, but are a constant feature at 10 d and thereafter. Multiple AC, presumably clonal, begin to evolve at 10 d and are consistent by 20 d, forming incipient microadenomata. We have examined 20 candidate chemopreventive agents for inhibition of AC. All agents were given in AIN-76 diet, at two dose levels, with injections of AOM. AC were measured after 5 weeks of growth. Among the most active AC-inhibiting agents were BHA, DFMO, quercetin, diallyl sulfide, 18 beta-glycyrrhetinic acid, and ascorbyl palmitate. In a post-initiation study, the differentiating agent sodium butyrate was ineffective, but piroxicam was highly effective in modulating AC growth. Further, piroxicam inhibited AC development at all stages of growth from single to polycryptal clusters of AC. The AC assay shows marked sensitivity and specificity for screening agents for chemoprevention of colon cancer.

Animals↗
PubMed1995

Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase?

Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potential as chemopreventive agents for colorectal cancer. Recent case-control drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/or decreased death rate from this disease. Several different NSAIDs reduce formation of both colon adenomatous polyps (the precursor lesion of colon cancer) and cancers in experimental animals given known carcinogens. Perhaps most convincing are reports that the NSAID sulindac promotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized pharmacologic effect of the NSAIDs is their reduction of prostaglandin synthesis by inhibiting prostaglandin synthetase PGE2, which catalyzes the formation of prostaglandin precursors from arachidonic acid. Several lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effects. Relatively high levels of prostaglandins have been reported to inhibit tumor cell growth both in vivo and in vitro, and to inhibit differentiation in some tumor cell lines. We evaluated comparative chemopreventive effects on colon tumor formation in an azoxymethane (AOM)-induced colon carcinogenesis rat model using the NSAIDs piroxicam, sulindac, and sulindac sulfone, a metabolite of sulindac which lacks the anti-prostaglandin synthetase activity typically associated with NSAID-induced gastrointestinal toxicities. The results demonstrate that sulindac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM-induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Chemoprevention of cancer by organoselenium compounds.

A major research goal of our laboratories is the development of new organoselenium cancer chemopreventive agents with less toxicity compared to some of the historical selenium compounds, such as sodium selenite. Ideally, such agents would be employed to inhibit tumor development in different organs caused by a variety of chemical carcinogens, particularly those present in the human environment. A series of organoselenium compounds has been synthesized and evaluated for their chemopreventive efficacy in vivo. Parallel to these studies, short-term in vitro and in vivo assays were employed to understand the mechanism of action and to rapidly evaluate their efficacy in eventual long-term preclinical investigations. We demonstrated that one of the most effective of these organoselenium compounds, 1,4-phenylenebis(methylene)selenocyanate (p-XSC, Fig. 1), is capable of inhibiting tumors in the mammary glands, colon, and lung of laboratory animals. Dietary p-XSC inhibited mammary tumor development induced by 7,12-dimethylbenz(a)anthracene (DMBA) during both the initiation and post-initiation phases of carcinogenesis in female CD rats. p-XSC inhibited DMBA-DNA adduct formation in the mammary glands. In collaboration with other laboratories, we demonstrated that p-XSC inhibited thymidine kinase in mammary tumor cell lines derived from both humans and rats. Employing mammary carcinoma cell lines, p-XSC was also shown to inhibit cell growth and induce a dose-dependent increase in cell death by apoptosis. In these assays p-XSC appears superior to selenite and to its sulfur analog, 1,4-phenylenebis(methylene)thiocyanate. Dietary p-XSC decreased colon tumor induction by azoxymethane in F344 rats during both phases of carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Use of in vitro assays to predict the efficacy of chemopreventive agents in whole animals.

Five in vitro assays have been applied to screen the efficacy of potential chemopreventive agents. These assays measure a) inhibition of morphological transformation in rat tracheal epithelial (RTE) cells, b) inhibition of anchorage independence in human lung tumor (A427) cells, c) inhibition of hyperplastic alveolar nodule formation in mouse mammary organ cultures (MMOC), d) inhibition of anchorage independence in mouse JB6 epidermal cells, and e) the inhibition of calcium tolerance in human foreskin epithelial cells. The efficacy of many of these same agents in whole animal studies of lung, colon, mammary gland, skin, and urinary bladder carcinogenesis has also been measured. The aim herein is to estimate the positive and negative predictive values of these in vitro assays against whole animal chemopreventive efficacy data using the same chemicals. For three of these assays--using RTE, A427 cells and mouse mammary organ culture (MMOC)-enough data are available to allow the estimate to be made. Such extrapolations of in vitro data to the in vivo situation are difficult at best. There are many dissimilarities between the two assay systems. The in vitro assays use respiratory and mammary epithelial cells, while the in vivo assays use respiratory, mammary, colon, bladder and skin cells. The in vitro assays use the carcinogens benzo(a)pyrene (B(a)P) and 7,12-dimethylbenz(a)anthracene (DMBA), while the in vivo assays use B(a)P, DMBA, N-methyl-N-nitrosourea (MNU), N,N'-diethylnitrosamine (DEN), azoxymethane (AOM), and N-butyl-N-(4-hydroxybutyl)nitrosoamine (OH-BBN). There are vast differences in pharmacodynamics and pharmacokinetics in vitro and in vivo, yet it is possible to rapidly screen chemicals in vitro for efficacy at one-tenth the cost and complete tests in weeks instead of months. A positive in vitro assay was defined as a 20% inhibition (compared with control) for the RTE and A427 assays and a 60% inhibition for the MMOC assay at nontoxic concentrations. For in vivo assays, the criterion for a positive result was a statistically significant inhibition of incidence, multiplicity or a significant increase in latency (mean time to first tumor). For an agent to be considered negative in animals, it required negative results in at least two different organ systems and no positive results. Using the battery of three in vitro tests, the positive predictive value for having one, two, or three positive in vitro assays and at least one positive whole animal test was 76%, 80%, and 83% respectively. The negative predictive values for one, two or all three in vitro assays was 25%, 27%, and 50%. From these data it is observed that in vitro assays give valuable positive predictive values and less valuable negative predictive values. The mechanisms of chemoprevention are not well understood. Seven categories of agents were examined for their cancer preventing both in vitro and in vivo: antiinflammatories, antioxidants, arachadonic acid metabolism inhibitors, GSH inducers, GST inducers, ODC inhibitors, and PKC inhibitors. Three or even five in vitro assays cannot be all-inclusive of the many mechanisms of cancer prevention. However, three assays help to predict whole animal efficacy with reasonable positive predictive values. Much work and development remains to be done to rapidly identify new chemopreventive drugs.

Animals↗
PubMed2004

Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancer.

Surrogate end-point biomarkers are being developed as indicators of the efficacy of chemopreventive agents. These biomarkers are molecular and biological end-points that can be modulated by chemopreventive agents in accordance with their efficacy to prevent cancer. DNA hypomethylation is a common alteration found in colon tumors that has the potential of being modulated by chemopreventive agents and thus being useful as a surrogate end-point biomarker. Agents that were either effective or ineffective in preventing colon cancer were evaluated for the ability to modulate DNA hypomethylation in azoxymethane-induced colon tumors in male F344 rats. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Colon tumors had a 70% reduction in DNA methylation relative to normal colonic mucosa. DNA methylation in the tumors was increased by 7 days of treatment with agents that have been shown to prevent colon cancer (calcium chloride, alpha-diflouromethylornithine [DFMO], piroxicam, and sulindac), whereas agents shown not to prevent colon cancer in rats (low dose aspirin, 2-carboxyphenyl retinamide [2-CPR], quercetin, 9-cis retinoic acid, and rutin) did not increase DNA methylation. The results suggest that the ability to reverse the DNA hypomethylation in colon tumors could be useful as a surrogate end-point biomarker for chemoprevention of colon cancer.

5-Methylcytosine↗
PubMed1995

No involvement of Ki-ras or p53 gene mutations in colitis-associated rat colon tumors induced by 1-hydroxyanthraquinone and methylazoxymethanol acetate.

1-Hydroxyanthraquinone (1-HA), which is present in some herbs, and methylazoxymethanol (MAM) acetate, a metabolite of azoxymethane, show synergistic carcinogenicity in rat colon, and 1-HA induces ulcerative changes with simultaneous severe inflammation of the entire colon. In this study, mutations in Ki-ras (exons 1 and 2) and p53 (exons 4-7) were studied by polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis. Of 18 adenomas and 38 adenocarcinomas induced in male F344 rats (52 tumors induced by 1-HA plus MAM acetate, three by 1-HA alone, and one by MAM acetate alone), no mutations in Ki-ras or p53 were detected under two conditions of PCR-SSCP analysis. Because human colon carcinomas from patients with ulcerative colitis have a very low incidence of Ki-ras mutation, this experimental system would be a good animal model of human colon carcinomas with ulcerative colitis and of human colon carcinomas without Ki-ras or p53 mutations.

Animals↗
PubMed1993

Protective mechanisms of dietary fibers in nutritional carcinogenesis.

Fibers in foods are complex carbohydrates. There are several types of fiber, but, for the purpose of mechanistic insight into their mode of protective action in carcinogenesis, classification into two broad types, soluble and insoluble fibers, is warranted. Soluble fibers are present in fruits, vegetables, and certain grains like oats. This type of fiber undergoes metabolism in the small intestine and especially in the large intestine through bacterial enzymes, converting it to products that increase stool size only moderately. But, they have appreciable effects in modifying the metabolism of colon carcinogens like azoxymethane to yield detoxified products and, thus, reducing colon carcinogenesis. In contrast, insoluble fibers present in sizeable amounts in bran cereals, like wheat or rice, are not significantly metabolized by enzymes in the intestinal flora. Such fibers increase stool size substantially through several mechanisms, including higher water retention. The larger bulk dilutes carcinogens, especially tumor promoters such as secondary bile acids, resulting in lower risk of colon cancer in animals and in humans. Evidence in animal models and in humans also indicates that fiber may lower the risk of breast cancer, possibly via an endocrine mechanism. Based on these concepts, increased intake of total fiber, but especially of wheat bran cereal fiber, to yield a daily stool in adults of about 200 grams can significantly reduce the risk of colon cancer and, to a lesser but definite extent, of breast cancer. Thus, adequate fiber intake from cereals, fruits, and vegetables can help prevent important types of human cancer.

Animals↗
PubMed1986

Deuterium isotope effects in carcinogenesis by N-nitroso compounds.

A number of N-nitroso compounds and an azoxyalkane have been labeled with deuterium in various positions and have been administered to rats, hamsters, or mice in parallel with the unlabeled compounds. The treatments with the labeled and analogous unlabeled compounds were equimolar and for the same time. Mortality rates from tumors and tumor incidences were compared between deuterium-labeled and the unlabeled analogs. In many cases more than one dose level was used for the comparisons. An increased rate of mortality from tumors or an increased incidence of induced tumors was considered an index of increased potency of one treatment compared with the other. Using these criteria deuterium in the alpha positions of nitrosodimethylamine, nitrosomorpholine, nitrosoheptamethyleneimine, and nitrosoazetidine reduced carcinogenic potency compared with the unlabeled compounds. This indicated that cleavage of a carbon-hydrogen bond in the alpha position was a rate-limiting step in carcinogenesis by these nitrosamines. In both nitrosomethylethylamine and nitroso-2,6-dimethylmorpholine, the presence of deuterium at different positions increased or decreased carcinogenic potency, suggesting that competition for oxidation between these sites might be the determining factor in activation of the molecule. This also applied to nitrosomethyl-n-butylamine and nitrosomethyl-phenylethylamine with deuterium at the methyl group or at the alpha carbon of the butyl or phenylethyl groups, and to azoxymethane with deuterium in the 1-methyl or 4-methyl group. In nitrosomethylcyclohexylamine, nitrosomethyl-n-dodecylamine, and dinitroso-2,6-dimethylpiperazine there was no detectable effect of deuterium on carcinogenic potency, suggesting that the conditions did not provide sufficient sensitivity for detection of an isotope effect, or that oxidation at the alpha carbon was not a rate-limiting step in carcinogenesis by these molecules.

Alkylation↗
PubMed1992

Experimental carcinogenesis at sutured and sutureless colonic anastomoses.

This study explores the role of sutures and the healing colonic wound in experimental carcinogenesis. One hundred sixty rats underwent surgery with colotomy and repair using silk, steel, or Vicryl (Ethicon, Somerville, NJ) sutures or a sutureless technique. Forty rats had a sham procedure. All animals received azoxymethane for 12 weeks at a dose of 10 mg/kg/week. Half the rats commenced carcinogen before surgery, and half commenced it eight weeks after surgery. Animals with anastomotic tumors were found in 46 percent of the sham group (P less than 0.05 cf. sutured), 41 percent of the sutureless group (P less than 0.02 cf. sutured), and 68 percent of the sutured group. The corresponding figures for anastomotic carcinoma were 9 percent (P less than 0.001 cf. sutured), 22 percent, and 38 percent. No significant differences in tumor yield were noted among the different sutures. However, several differences were noted between the two carcinogen models. In those animals that received surgery first, there was a higher incidence of anastomotic tumors (P less than 0.002) and cancers (P less than 0.0001) in the sutured and sutureless groups, and those tumors that occurred in the sutured group were considerably larger than in those that had carcinogen first (15.9 mm cf. 4.9 mm; P less than 0.0001). Overall, all sutures seem to enhance anastomotic tumor formation, and we would suggest that a sutureless anastomosis may diminish this risk.

Anastomosis, Surgical↗
PubMed1997

Use of intraperitoneal 5-fluorouracil and chlorhexidine for prevention of recurrence of perforated colorectal carcinoma in a rat model.

PURPOSE: Colorectal cancer is a prevalent and mortal disease, resulting in nearly 55,000 deaths in the United States annually. Preoperative or intraoperative spillage of tumor cells because of perforation occurs in up to 10 percent of cases. When this spillage occurs, the chance of recurrence and death is dramatically increased. METHODS: In an effort to reduce the chance of recurrence and death, we used a rat model to evaluate the efficacies of intraperitoneal 5-fluorouracil and chlorhexidine in reducing the incidence of recurrence. Rats were injected with 10 mg/kg azoxymethane subcutaneously weekly for 12 weeks to induce colorectal cancers. At 20 weeks, subtotal colectomies were performed on rats with colorectal tumors and without peritoneal implants or liver metastases. At the time of surgery, a cut portion of the tumor was placed in the abdomen for 30 minutes; the rats then randomly received peritoneal irrigation with 5-fluorouracil, chlorhexidine, or sterile water (control). Eight weeks postoperatively a necropsy was performed. At that time, obvious and suspected recurrences and the anastomotic area were sampled for histologic evaluation. RESULTS: Significant differences were seen with chlorhexidine vs. water for gross tumor (P = 0.05) and microscopic tumor (P < 0.05). 5-Fluorouracil showed a greater rate of abscess formation vs. both control and chlorhexidine (P > 0.05). CONCLUSIONS: Use of chlorhexidine intraperitoneal therapy at the time of the operation for perforated colorectal cancer significantly decreases the frequency of gross tumor recurrence but not total recurrences. Intraperitoneal 5-fluorouracil does not significantly decrease recurrence and may increase the risk of abscess when used intraoperatively.

Animals↗
PubMed1993

Effect of high fat corn oil, olive oil and fish oil on phospholipid fatty acid composition in male F344 rats.

Epidemiological and laboratory animal model studies have provided evidence that the effect of dietary fat on colon tumorigenesis depends on the amount of fat and its composition. Because of the importance of the composition of dietary fat and of tissue membrane fatty acid composition in tumor promotion, experiments were designed to investigate the relative effects of high fat diets rich in omega 3, omega 6 and omega 9 fatty acids and colon carcinogen on the phospholipid fatty acid composition of liver, colon, small intestine, erythrocytes and blood plasma. At 6 wk of age, groups of animals were fed diets containing 5% corn oil (LFCO), 23.5% corn oil (HFCO), 23.5% olive oil (HFOO), and 20.5% fish oil plus 3% corn oil (HFFO). Two weeks later all the animals except the vehicle-treated animals received azoxymethane s.c. once weekly for 2 wk at a dose rate of 15 mg/kg body weight. Animals were sacrificed 5 d later and liver, colon, small intestine and erythrocytes and blood plasma were analyzed for phospholipid fatty acids. The results indicate that the phospholipid fatty acid composition of liver, colon and small intestine of HFCO diet fed animals, were not significantly different from those fed the LFCO diet. The levels of palmitoleic acid and linoleic acid were increased in erythrocytes and blood plasma of the animals fed the HFCO diet compared to those fed the LFCO diet. Feeding the HFOO diet significantly increased the oleic acid content and decreased the linoleic acid and arachidonic acid levels in various organs when compared to the HFCO diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of dietary fat on colonic protein kinase C and induction of aberrant crypt foci.

A major objective of the present study was to determine whether a high-fat diet affects early events during colon carcinogenesis. Female Sprague-Dawley rats were injected with saline or azoxymethane (20 mg/kg) and fed either a normal (5% corn oil w/w) or a high (5% corn oil and 15% beef tallow w/w) fat diet. To assess the effect of a known tumor-promoting diet on the early events of neoplastic transformation, Study 1 examined the induction and growth of aberrant crypt foci (ACF) as well as of proliferative indices. The total number of ACF were similar in both groups even after 8 wk of dietary treatment; however, ACF with accelerated growth characteristics (> or = 4 crypts/focal lesion) were more prevalent (P < or = 0.05) in the colons of animals fed the high-fat diet. Metaphase arrest cells and 5'-bromo-2'-deoxyuridine labelled cells showed no appreciable response to dietary changes. To determine whether changes in colonic signal transduction pathways represent an early response to dietary modification, Study 2 evaluated the activity of protein kinase C (PKC), proliferative indices and changes in phospholipid fatty acid profiles. In comparison to the normal fat group, the colons of high-fat fed animals exhibited higher (P < or = 0.05) membranes and lower soluble PKC activity; however, proliferation patterns of these colons were not altered. Changes in the membrane lipid composition were minor; however, an increase in the phosphatidylcholine/phosphatidylethanolamine ratio and in 20:4n-6 was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Effect of polyphenolic extracts from red wine and 4-OH-coumaric acid on 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.

BACKGROUND: Total polyphenolic extracts from red wine protect against azoxymethane (AOM)-induced colon carcinogenesis in rats. Since red wine contains more than 200 different polyphenolic compounds, it is still unclear which substances are responsible for this effect. AIM OF THE STUDY: We investigated the effect of high molecular weight polyphenols (HMWP), low molecular weight polyphenols (LMWP) and total polyphenolic extracts from red wine (WE) on colon carcinogenesis. We also tested the effect of 4-OH-coumaric acid, a potent phenolic antioxidant present in wine and fruit. METHODS: F344 rats were treated weekly with 1,2-dimethylhydrazine (DMH) (30 mg/kg b.w. subcutaneously x 10 times). One week after the final DMH injection rats were divided into five groups and fed: a) a high fat (HF) diet containing 23% corn oil (w/w), as control or the same basal diet supplemented with b) 0.11 % (w/w) WE; c) 0.027% (w/w) HMWP d) 0.083% (w/w) LMWP or e) 0.1 % (w/w) 4-OH-coumaric acid. The dietary treatments continued until sacrifice, 16 weeks after the last DMH injection. RESULTS: WE treated rats had significantly fewer (p < 0.05) colorectal adenomas than controls, while rats in other treatment groups did not differ significantly from controls (colorectal adenomas/rat were: 2.2 +/- 0.3; 1.4 +/- 0.2; 2.9 +/- 0.5; 2.6 +/- 0.4; 2.3 +/- 0.3; in controls, WE, HMWP, LMWP and 4-OH-coumaric acid groups, respectively; means +/- SE). The mean number of colorectal carcinomas per rat was similar among all experimental groups. Proliferative activity in the normal colon mucosa did not vary among experimental groups. CONCLUSIONS: Total polyphenolic extracts (WE) from red wine, but neither the HMWP nor the LMWP, have some inhibitory effect on the process of colon carcinogenesis by DMH reducing the number of adenomas.

1,2-Dimethylhydrazine↗
PubMed1999

Effect of complex polyphenols on colon carcinogenesis.

BACKGROUND: Complex polyphenols and tannins from wine (WCPT) are being considered increasingly as potential cancer chemopreventive agents, since epidemiological studies suggest that populations consuming a high amount of polyphenols in the diet may have a lower incidence of some types of cancer. AIM OF THE STUDY: We studied the effect of WCPT on a series of parameters related to colon carcinogenesis in rats. METHODS: WCPT were administered to F344 rats at a dose of 14 or 57 mg/kg/d, mixed with the diet. The higher dose is about ten times the exposure to polyphenols of a moderate drinker of red wine. In rats treated with WCPT, we measured fecal bile acids and long chain fatty acids, colon mucosa cell proliferation, apoptosis and, after administration of colon carcinogens, the number and size of aberrant crypt foci (ACF) and nuclear aberrations. RESULTS: Colon mucosa proliferation was not varied by chronic administration (90 d) of WCPT (14 or 57 mg/kg/d). The highest dose of WCPT decreased the number of cells in the colon crypts, but did not increase apoptosis. WCPT (57 mg/kg) administered before or after the administration of azoxymethane (AOM) did not vary the number or multiplicity of ACF in the colon. The number of nuclear aberrations (NA) in colon mucosa was studied after administration of 1,2-dimethylhydrazine (DMH) and 2-amino-3-methylimidazo (4,5-f)quinoline (IQ), colon-specific carcinogens which require metabolic activation. The effect of DMH and IQ was not varied by pre-feeding WCPT (57 mg/kg) for 10 d. Similarly, the levels of total, secondary bile acids and long chain fatty acids did not varied significantly in animals fed WCPT for 90 d. CONCLUSIONS: WCPT administration does not influence parameters related to colon carcinogenesis in the rat.

Animals↗
PubMed2005

The influence of specific luminal factors on the colonic epithelium: high-dose butyrate and physical changes suppress early carcinogenic events in rats.

INTRODUCTION: Although luminal delivery of butyrate is one putative mechanism by which biology of the colonic epithelium might be influenced by changes in luminal contents, there is a paucity of supportive cause-effect evidence. This study aimed to directly establish whether distal colonic butyrate delivery is able to alter the response of the distal colonic epithelium to a carcinogen. METHODS: Groups of male Sprague-Dawley rats with chronically intubated colons received infusions of 80 mM butyrate or 0.9 percent saline into distal colon two or five times daily. Three weeks after exposure to azoxymethane (15 mg/kg subcutaneously), the density of aberrant crypts was quantified in distal colon. RESULTS: Infusions of 0.5 ml twice daily, whether containing saline or butyrate, decreased the number of aberrant crypt foci by 45 percent compared with rats receiving no infusions (P = 0.004, analysis of variance). Similar results were obtained when infusions were restricted to the post-initiation phase. When infusions were increased to 1 ml five times daily, saline infusions similarly suppressed aberrant crypt formation (38 percent), but butyrate infusions suppressed it to a greater degree (by 64 percent; P = 0.02 compared with saline infusion, t-test). CONCLUSIONS: High levels of butyrate delivery to the distal colonic lumen alter the epithelial response to a carcinogen in otherwise healthy rats. This finding directly supports the notion that the effects of butyrate on cells in vitro do occur in vivo provided a sufficient dose is delivered. The effect of infusion of liquid per se on the epithelial response highlights the potential impact physical changes alone can have on the colonic epithelium.

Animals↗