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PubMed1997

Chemoprevention of colon carcinogenesis by dietary perillyl alcohol.

Epidemiological studies suggest that consumption of diets containing fruits and vegetables, major sources of phytochemicals and micronutrients, may reduce the risk of developing cancer of the colon. Several phytochemicals and micronutrients present in fruits and vegetables are known to exert cancer-chemopreventive effects in several organs, including the colon. Monoterpenes such as d-limonene and perillyl alcohol derived from orange peels and lavender, respectively, have been shown to possess chemopreventive properties against mammary, liver, and/or lung carcinogenesis. The present study was designed to investigate the efficacy of dietary 40 and 80% maximum tolerated dose (MTD) levels of perillyl alcohol on azoxymethane (AOM)-induced colon carcinogenesis. The effect of this agent on the process of apoptosis in colon tumors was also investigated. Prior to the efficacy study, the MTD of perillyl alcohol was determined in male F344 rats in a 6-week subchronic toxicity study and found to be a 2.5-g/kg diet when added to the AIN-76A diet. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or diets containing 1 and 2 g perillyl alcohol/kg diet, representing 40 and 80% MTD levels, respectively. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of AOM (15 mg/kg body weight/week). All animals were continued on their respective dietary regimen for 52 weeks after AOM treatment and then sacrificed. Colon tumors were evaluated histopathologically using routine procedures. Perillyl alcohol at the 1-g/kg level significantly inhibited the incidence (percentage of animals with tumors) and multiplicity (tumors/ animals) of invasive adenocarcinomas of the colon, whereas perillyl alcohol at 2 g/kg diet inhibited the incidence of total adenocarcinomas of the colon and small intestine as compared to the control diet. Our studies also indicate that the colon tumors of animals fed perillyl alcohol exhibited increased apoptosis as compared to those fed the control diet. These results demonstrate the potential chemopreventive activity of perillyl alcohol against colon carcinogenesis. The chemopreventive activity of perillyl alcohol is mediated through the tumor cell loss by apoptosis.

Adenocarcinoma↗
PubMed1997

Modulation of apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and promotion.

Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate through induction of cell death by apoptosis. This study tested the hypothesis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of tumor promoters. The present study was designed to investigate whether the chemopreventive properties of sulindac, curcumin, and phenylethyl-3-methylcaffeate (PEMC) and the tumor-promoting activity of 6-phenylhexyl isothiocyanate (PHITC) that were observed in our previous studies are associated with the induction or inhibition of apoptosis in azoxymethane (AOM)-induced colon tumors in male F344 rats. At 5 weeks of age, groups of rats were fed control (modified AIN-76A) diet or diets containing 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, or 640 ppm of PHITC. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given AOM (15 mg/kg body weight) once weekly for 2 weeks. To study the effect of sulindac administered during promotion/progression stage, the rats were fed the control diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment. The rats were sacrificed 52 weeks after carcinogen treatment, and their colonic tumors were subjected to histopathological evaluation and the appearance of apoptosis. In the current study, chronic administration of sulindac, curcumin, and PEMC or sulindac given only during promotion/progression significantly increased the apoptotic index (percentage of apoptosis) as compared to administration of the control diet; the apoptotic indices in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during promotion/progression stage, the apoptotic index was 19.1%. However, dietary PHITC blocked the process of apoptosis during colon carcinogenesis. The apoptotic index in PHITC diet was 7.0%. Taken together, our data show that chemopreventive properties of agents are correlated with the degree of apoptosis. Therefore apoptosis seems to be a reliable biomarker for the evaluation of potential agents for cancer prevention.

Adenocarcinoma↗
PubMed1996

Colon cancer in rats and diet in the Sonoran desert region of Mexico.

The role of dietary fiber in colon cancer is still not clear. Epidemiological studies suggest a protective role for high fiber intake. However the data suggest that the effects of fiber must be considered in the context of the total diet and its interactions with other dietary components. The typical Sonora diet is high in dietary fiber (7.8%) and the majority of this fiber (71%) is insoluble. Comparing the incidence of colon cancer in Sonora with its neighboring state of Arizona, in 1991, Sonora reported 40 cases of colon cancer, a population of 1,823,606, compared to 1432 for Arizona (3,763,322 inhabitants). The typical regional diet was evaluated for its protective effect in the development of colon cancer in rats injected with azoxymethane, AOM. The regional diet showed a tendency to protect against colon cancer, an incidence of 45% compared to 66% for the control diet, although this effect was not significant (p = 0.15). Further studies are needed to fully evaluate the diet and certain interactive dietary factors such as fat, quantity as well as type, protein, calcium and antioxidant nutrients.

Animals↗
PubMed1997

Dietary fat and colon cancer: modulation of cyclooxygenase-2 by types and amount of dietary fat during the postinitiation stage of colon carcinogenesis.

Several epidemiological and experimental studies have indicated a strong relationship between different types of dietary fats and risk of colon cancer. However, the modulating effects of these nutritional factors at the molecular level are not fully elucidated. It has been documented that the modulation of tumorigenesis is associated with changes in the levels of prostaglandins production. To provide an understanding of the mechanism(s) of dietary fat-induced modulation of colon tumor development, we have analyzed the expression of cyclooxygenase (COX), an enzyme that catalyzes the metabolism of omega-3 and omega-6 polyunsaturated fatty acids in a critical step in prostaglandin biosynthesis. Male F344 rats were fed the semipurified AIN-76A diet containing low-fat corn oil and were s.c. injected azoxymethane (AOM) dissolved in normal saline at a dose rate of 15 mg/kg of body weight, once weekly, for 2 weeks. Vehicle controls received s.c. equal volumes of normal saline. One day after the second AOM or saline injection, rats intended to receive experimental diets were provided high-fat corn oil (HFCO) or high-fat fish oil (HFFO) mixed in semipurified AIN-76A diet, and the remaining rats continued to receive the low-fat corn oil diet. Animals were sacrificed 1, 12, or 36 weeks after the last AOM or saline injection, and their colonic mucosa, as well as the grossly visible colon tumors from rats sacrificed 36 weeks after the last AOM injection, were analyzed for the expression levels of COX-1 and COX-2. The results indicate that AOM induced increasingly high levels of COX-2 expression with advancing stages of colon tumorigenesis. HFCO further enhanced the AOM-induced COX-2 expression. In contrast, HFFO ingestion resulted in a significant decrease in COX-2 expression both in the colonic mucosa and in tumors. These results correlate with increased incidence and multiplicity of grossly visible colon tumors in AOM-treated animals that were fed the HFCO diet versus decreased tumor incidence and lower tumor multiplicity in animals that were fed the HFFO diet. No significant differences were observed in expression levels of COX-1. The data suggest that HFCO may promote colon tumorigenesis by up-regulating the COX-2 expression, whereas HFFO may exert its antitumor effect by inhibiting the COX-2 expression.

Animals↗
PubMed1997

Enhancement of experimental colon cancer by genistein.

Several phytochemicals and micronutrients that are present in fruits and vegetables are known to exert cancer chemopreventive effects in several organs, including the colon. Among them, the soybean isoflavonoid genistein received much attention due to its potential anticarcinogenic, antiproliferative effects and its potential role in several signal transduction pathways. The present study was designed to investigate the effect of genistein on azoxymethane (AOM)-induced colon carcinogenesis and to study its modulatory role on the levels of activity of 8-isoprostane, cyclooxygenase (COX), and 15-hydroxyprostaglandin F2alpha dehydrogenase (15-PGDH) in the colonic mucosa and colon tumors of male F344 rats. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or a diet containing 250 ppm genistein. Beginning 2 weeks later, all animals except those in the vehicle-treated groups were given weekly s.c. injections of AOM (15 mg/kg body weight) for 2 successive weeks. All rats were continued on their respective dietary regimen for 52 weeks after AOM treatment and were then sacrificed. Colon tumors were evaluated histopathologically. Colonic mucosae and tumors were analyzed for COX, 15-PGDH, and 8-isoprostane levels. Administration of genistein significantly increased noninvasive and total adenocarcinoma multiplicity (P < 0.01) in the colon, compared to the control diet, but it had no effect on the colon adenocarcinoma incidence nor on the multiplicity of invasive adenocarcinoma (P > 0.05). Also, genistein significantly inhibited the 15-PGDH activity (>35%) and levels of 8-iosoprostane (50%) in colonic mucosa and in tumors. In contrast, genistein had no significant effect on the COX synthetic activity, as measured by the rate of formation of prostaglandins and thromboxane B2 from [14C]arachidonic acid. The results of this investigation emphasize that the biological effects of genistein may be organ specific, inhibiting cancer development in some sites yet showing no effect or an enhancing effect on the tumorigenesis at other sites, such as the colon. The inhibition of 8-isoprostane levels by genistein indicates its possible antioxidant potential, which is independent of the observed colon tumor enhancement, yet this agent may also possess several biological effects that overshadow its antioxidant potential. The exact mechanism(s) of colon tumor enhancement by genistein remain to be elucidated; it is likely that its colon tumor-enhancing effects may, at least in part, be related to inhibition of prostaglandin catabolic enzyme activities.

Adenocarcinoma↗
PubMed1997

The role of apoptosis in the modulation of colon carcinogenesis by dietary fat and by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

Studies in laboratory animals have demonstrated that dietary supplements of organoselenium, 1,4-phenylenebis(methylene)selenocyanate (p-XSC) inhibit colon carcinogenesis. Diverse chemopreventive agents and clinically used anticancer drugs have been shown to induce apoptosis in colonic tumors. Inducing apoptosis is a key mechanism for the effectiveness of some chemopreventive agents; however, failure of apoptosis is now believed to contribute to the development of human cancer. In this study, we determined the number of apoptotic bodies in the colon tumors of rats fed a low-fat (LF) or a high-fat (HF) diet with or without p-XSC treatment. At 5 weeks of age, male F344 rats were divided into four groups, which were then maintained on one of the following diets: LF, 5% corn oil; HF, 23.5% corn oil; and LF and HF supplemented with 20 ppm p-XSC. In addition, the LF or HF diet with p-XSC supplements was administered either during the initiation stage or postinitiation. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given 15 mg/kg of body weight of azoxymethane once weekly for 2 weeks. The animals were sacrificed 38 weeks after carcinogen treatment, and their colonic tumors were examined for appearance of apoptosis. The LF diet significantly increased the percentage of apoptosis as compared to the HF diet; the percentage of apoptosis in LF and HF diets were 12.4 and 2.9. The colon tumors that were present in the groups fed p-XSC together with a LF or a HF diet after carcinogen administration (postinitiation period) had a higher number of apoptotic bodies than those that were present in the animals fed p-XSC before carcinogen treatment (initiation period). The extent of apoptosis was weak when p-XSC was given with a HF diet (4.4%) during the initiation phase, but it was high significant when p-XSC was administered with LF diet (25.2%). Taken together, our data suggest that administration of LF diet supplemented with p-XSC increases apoptosis as compared to a HF diet alone.

Animals↗
PubMedDate not supplied

Cell death and cell proliferation contribute to the enhanced growth of foci by fasting in rat medial colon.

We have recently shown that fasting before initiation markedly stimulated the growth of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in the rat medial colon. Here we investigated the mechanisms by which fasting enhanced the growth of ACF. Rats were exposed to 4 day-starvation, then they were given AOM (20 mg/kg) on the first day of refeeding. 4 day-fasting depressed cell proliferation as shown by the decreased mitotic index and enhanced cell death by apoptosis. On the first day of refeeding, apoptotic index remained higher than control values, while mitotic index markedly increased in the colonic epithelium of fasted/ refed rats. The administration of AOM induced an apoptotic wave, that was higher in controls, and a transient drop in the mitotic index that recovered quickly in the fasted/refed group. These data suggest that starvation-induced apoptosis represents the mitogenic stimulus to increase the rates of cell proliferation responsible for the enhanced growth of ACF in fasted/refed rats.

Animals↗
PubMed1998

Prevention of colon cancer by pre- and probiotics: evidence from laboratory studies.

Oligofructose and inulin, selective fermentable chicory fructans, have been shown to stimulate the growth of bifidobacteria which are regarded as beneficial strains in the colon. Studies were designed to evaluate inulin (Raftiline) and oligofructose (Raftilose), for their potential inhibitory properties against aberrant crypt foci (ACF) formation in the colon of rats. ACF are putative preneoplastic lesions from which adenomas and carcinomas may develop. The results of this study demonstrate that dietary administration of oligofructose and inulin inhibits the formation of preneoplastic lesions in the colon suggesting the potential colon tumour inhibitory properties of chicory fructans. Since these prebiotics selectively stimulate the growth of bifidobacteria, tumour inhibitory activity of lyophilized cultures of Bifidobacterium longum (BL) against azoxymethane (AOM)-induced colon carcinogenesis in rats and modulating effect of these cultures on colonic tumour cell proliferation, ornithine decarboxylase (ODC) activity, and ras-p21 oncoprotein expression were investigated. Dietary administration of lyophilized cultures of BL strongly suppressed AOM-induced colon tumour development. Inhibition of colon carcinogenesis was associated with a decrease in colonic mucosal cell proliferation and colonic mucosal and tumour ODC and ras-p21 activities.

Animals↗
PubMed1997

Gene expression changes associated with chemically induced rat mammary carcinogenesis.

Experimentally induced models of breast carcinogenesis in the rat are widely used for studying the biology of breast cancer and for developing and evaluating cancer prevention and control strategies. However, very little is known about gene expression changes that are associated with experimentally induced mammary carcinogenesis. This paper reports the identification, by differential display of mRNA and molecular cloning, of seven cDNA fragments of gene transcripts overexpressed in mammary carcinomas induced by 1-methyl-1-nitrosourea. These genes included the rat homologues of human galectin-7 gene, the human/mouse melanoma inhibitory activity/bovine chondrocyte-derived retinoic acid sensitive protein gene, the mouse stearoyl-CoA desaturase-2 gene, and the mouse endo B cytokeratin/human cytokeratin-18 gene. Although each of these genes has been implicated in some aspect of carcinogenesis in other organs, this paper is the first report of their overexpression in chemically induced mammary carcinomas. Two previously uncharacterized gene transcripts were also identified. A comparison of the expression levels of several genes in mammary carcinomas with those in the normal mammary gland tissue of virgin rats, mid-stage pregnant rats, and of day 1 postpartum lactating dams indicated that the overexpression of several genes observed in mammary carcinomas could not be accounted for by either a difference in the mammary epithelial content between mammary carcinoma and normal mammary tissue or by mammary epithelium-specific proliferation associated with pregnancy. Several genes were also overexpressed in rat mammary carcinomas induced by 7,12-dimethylbenz[a]anthracene but not in azoxymethane-induced rat colon adenocarcinomas. The genes identified in this study may therefore represent mammary carcinoma-specific molecular markers that may be helpful in investigations of mammary carcinogenesis and its prevention.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1975

Role of bile metabolites in colon carcinogenesis. Animal models.

Epidemiological data indicate that colon cancer incidence is associated mainly with high dietary fat intake. Studies in metabolic epidemiology have shown a strong association between dietary fat intake, level of fecal bacteria, fecal acid, and neutral sterols, and the risk of colon cancer among different populations. Current concepts visualize that colonic bile acids and cholesterol metabolities play a modifying role in large bowel carcinogenesis, and that these compounds are derived from dietary factors, directly or indirectly, and subsequently are modified by the intestinal bacteria. In animal models, lithocholic acid and dexycholic acid, which are present in high concentration in the large bowel of man, acted as promoters of colon carcinogenesis. The carcinogenic effect of azoxymethane in rats was enhanced by the increase of bile salts in the colon induced by surgical means. Animals fed a high fat diet were more susceptable to colon tumor induction by dimethylhydrazine compared with rats fed a normal diet. Our data also demonstrate that the intestinal microflora played a modifying role in accelerating colon tumor production by dimethylhydrazine.

Animals↗
PubMed1980

Mutagenesis within the gastrointestinal tract determined by histidine auxotrophs of Salmonella typhimurium.

The Ames Salmonella mutants can be maintained for months within the gastrointestinal tract of otherwise germfree rats. The ingestion of various carcinogens, but not structurally related non-carcinogens, results in an increased concentration of his+ revertants in the feces. Rats, associated with strain TA1538, were also associated with either L. plantarum of B. vulgatus and with both of these strains. After 2-nitrofluorene ingestion (3.4 mg) the concentration of fecal revertants increased except in rats associated only with strains TA1538 and B. vulgatus. The concentration of B. vulgatus. The concentration of B. vulgatus in the stomach of individual rats correlated negatively with their response to 2-nitrofluorene. Since only B. vulgatus reduces nitrofluorene to the less mutagenic 2-aminofluorene, it appears that B. vulgatus diminishes the revertant response by metabolic removal of the more potent direct acting mutagen from the gut. The ingestion of 1,2-dimethylhydrazine (21 mg/kg) and azoxymethane (19 mg/kg) provokes increased fecal revertants only in some animals associated with strain TA1535 or TA100.

Animals↗
PubMed2000

Chemopreventive effects of coffee bean and rice constituents on colorectal carcinogenesis.

Polyphenolic compound chlorogenic acid (CGA) known to be much contained in coffee beans was found to have a regressive effect on induced aberrant crypt foci (ACF) as well as on development of ACF in azoxymethane (AOM)-induced colorectal carcinogenesis in rats. Rice germ and gamma-aminobutyric acid-enriched defatted rice germ inhibited AOM-induced ACF formation and colorectal carcinogenesis in rats. Ferulic acid (FA) also known to be contained in coffee beans and rice prevented AOM-induced ACF formation and intestinal carcinogenesis in rats. Both of food factors, coffee and rice may be of benefit to prevention of human colorectal cancers.

Animals↗
PubMed2000

Recent studies on the biofunctions and biotransformations of curcumin.

Curcumin is a major component of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NFkappaB and the expressions of c-jun, c-fos, c-myc and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydro-curcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are major metabolites of curcumin in mice.

Animals↗
PubMed1987

Inhibition of intestinal carcinogenesis by dietary supplementation with calcium.

Dietary supplementation with calcium reduces colonic crypt cell production rates in both normal and hyperplastic mucosa. Calcium can bind intraluminally with bile salts and fatty acids thus reducing their mitogenic effect. The protective role of oral calcium on intestinal carcinogenesis (induced by azoxymethane) was tested in 60 male Sprague-Dawley rats submitted to either 80 per cent mid jejuno-ileal resection (n = 30) or jejunal transection (n = 30). Half the rats in each group received calcium lactate 24 g/l added to their drinking water. Rats were killed 25-27 weeks postoperatively. Enterectomy increased colonic tumour yield by 60-106 per cent (P = 0.002-0.005) and duodenal tumour yield by 70-86 per cent. Calcium abolished this effect at both sites, halving intestinal tumour yields in rats with both transection and resection (P less than 0.05). Doubling the dietary intake of calcium inhibits experimental carcinogenesis.

Adenoma↗
PubMed1991

Suture technique affects perianastomotic colonic crypt cell production and tumour formation.

Suture line recurrence is an important cause of failure after potentially curative resection for colonic carcinoma. Our aim was to determine whether suture technique affected the incidence of perianastomotic tumours in experimentally induced colonic cancer. Sprague-Dawley rats were randomized into three groups. A 1 cm longitudinal colotomy was repaired with four interrupted 6/0 polypropylene monofilament sutures, using either a transmural technique (n = 18) or a seromuscular technique (n = 18). Control animals (n = 18) had a sham laparotomy. All animals received nine, weekly, subcutaneous injections of azoxymethane (total dose 90 mg/kg) starting 6 weeks after laparotomy. Surviving animals were killed 32 weeks after laparotomy. Five animals from each group were given intraperitoneal bromodeoxyuridine (100 mg/kg) 1 h before being killed. At death, perianastomotic tumours occurred more frequently in animals with transmural sutures than in either controls or those with seromuscular sutures. This difference was associated with a greater mucosal bromodeoxyuridine crypt cell labelling index in the transmural suture group. We conclude that a transmural anastomotic suture technique promotes the development of experimental perianastomotic colonic tumours.

Anastomosis, Surgical↗
PubMed1982

Detection of genotoxic carcinogens in the in vivo-in vitro hepatocyte DNA repair assay.

The in vivo-in vitro hepatocyte DNA repair assay has been shown to be useful in the evaluation of the carcinogenic potential of chemicals. The purpose of this study was to apply this assay to determining the genotoxicity of the compounds from a wide variety of structural classes. Male Fischer-334 rats were treated by gavage or ip injection with compounds dissolved in either corn oil, water, or dimethyl sulfoxide (DMSO). At selected times after treatment, hepatocytes were isolated by liver perfusion and cultured with 3H-thymidine, Unscheduled DNA synthesis (UDS) was measured by quantitative autoradiography as net grains/nucleus (NG); greater than or equal to 5 NG was considered positive. Water, corn oil, or DMSO controls produced -3 to -6 NG with less than or equal to 6% of the cells in repair. All genotoxic hepatocarcinogens tested produced strong positive responses of greater than 15 NG including dimethylnitrosamine, 2-acetylaminofluorene (2-AAF), azoxymethane, 1,2-dimethylhydrazine, benzidine, aflatoxin B1, 2,6-dinitrotoluene, and 2,4-diaminotoluene. The noncarcinogen, 2,6-diaminotoluene, was negative. The mutagen and rat brain carcinogen methyl methanesulfonate (MMS) and the rat pancreatic carcinogen azaserine were also positive. The carcinogens benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene yielded from -2 to -4 NG. This negative response is consistent with their lack of carcinogenic activity in rat liver. MMS produced the greatest amount of UDS 2 hr after treatment whereas 2-AAF did not induce its maximum response until 12 hr post-treatment. The potent hepatotoxin carbon tetrachloride induced a 40-fold elevation in DNA replication 48 hr after a 400 mg/kg dose, but no UDS was observed at 2, 12, 24, or 48 hr post-treatment. The weak hepatocarcinogen safrole induced no UDS suggesting that it is either nongenotoxic or is metabolized to an active form at an extremely slow rate following a single administration. These results demonstrate that this assay is valuable for the detection and study of a variety of genotoxic carcinogens.

Animals↗
PubMed1982

Detection of DNA damage in primary cultures of rat hepatocytes following in vivo and in vitro exposure to genotoxic agents.

A simplified method for the quantitation of DNA damage in nonlabeled hepatocytes, using a fluorometric technique for the quantitation of DNA in conjunction with a modification of the alkaline elution technique of Kohn et al [1976], following chemical treatment in vitro and in vivo, is described. Freshly isolated hepatocytes were treated in vitro with 2-acetylaminofluorene, aflatoxin B1, and dimethylnitrosamine, then examined for DNA damage. Exposure to each of these compounds resulted in DNA damage. Hepatocytes isolated from rats treated with the hepatocarcinogens 2-acetylaminofluorene, benzidine, azoxymethane, dimethylhydrazine, dimethylnitrosamine, and diethylnitrosamine sustained DNA damage as evidenced by increased alkaline elution. DNA damage in hepatocytes was also observed as a result of treatment with methylmethanesulfonate and azaserine. The hepatotoxin carbon tetrachloride did not induce DNA damage in hepatocytes isolated from treated animals. A comparison of the induction of DNA damage and of unscheduled DNA synthesis in hepatocytes from the same animals revealed that in most cases the extent of elution of DNA from filters was proportional to the induction of DNA repair.

Aflatoxin B1↗
PubMed2001

Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention of colon cancer has been hindered by their potential gastro-intestinal toxicity. Nabumetone, which is approximately 10 to 36 times safer than conventional NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-dependent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resulting in 15% and 37% reductions, respectively (p < 0.05). Moreover, complex ACF were reduced by 48% in the latter group. MIN mice studies confirmed the chemopreventive efficacy of nabumetone, with 900 ppm suppressing approximately half of the intestinal tumors. Interestingly, inhibition of intermediate biomarkers in both models was markedly greater in the distal than the proximal bowel. To mechanistically evaluate this regional selectivity, we assessed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and demonstrated a 3- to 4-fold excess in the distal relative to the proximal bowel in both MIN mice and AOM-treated rats. We then investigated another putative NSAID target, peroxisome proliferator-activated receptor-delta (PPAR-delta) and demonstrated up-regulation during AOM-induced colonic tumorigenesis. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR-delta in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The striking distal predilection of nabumetone may be, at least partially, explained by distal bowel over-expression of COX-2 and PPAR-delta.

Animals↗