Experimental colon carcinogenesis is facilitated by endogenous factors in the intestinal contents

The theory that endogenous factors in the intestinal contentsmay be pathogenic during large bowel carcinogenesis was testedin the dimethylhydrazine (DMH)-induced rat colon cancer model.Thirty female Wistar rats, each serving as their own control,had a surgical transection of the proximal colon with reanastomosisto the rectum, thereby excluding part of the colon from faecalcontact. All rats then received a course of DMH (40 mg/kg bodywt/wk s.c. for 10 weeks) while fed on Vivonex. This diet wasselected because it lacks known exogenous (dietary) cocarcinogens.It also produces mucosal atrophy in functioning (proximal) colon,to parallel the disuse atrophy induced in the defunctioned (distal)colon. Animals remained on the diet throughout the experimentand were killed when moribund or at 40 weeks. At necropsy, theanatomical distribution, number, size and histological typeof colon tumours were compared between functioning and defunctionedcolonic segments within the same animal. At autopsy, there weresignificantly fewer colon tumours in the defunctioned segment(P < 0.005). Furthermore, there were significantly fewercarcinomas (P <0.005) and fewer tumours >1 cm diameter(P <0.01) in this segment. The data indicate that endogenousfactors in the intestinal contents facilitate chemically-inducedcolon carcinogenesis. Luminal nutrition may be implicated.     

Black tea and mammary gland carcinogenesis by 7,12- dimethylbenz[a]anthracene in rats fed control or high fat diets

Epidemiological studies suggest that tea may reduce cancer risk, and in laboratory rodents, chemopreventive effects of tea or purified extracts of tea have been demonstrated in lung, gastrointestinal tract and skin. There is some evidence of chemoprevention by tea in the mammary gland, but the data are not conclusive. In order to evaluate more fully the possible influence of black tea on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary gland tumors in the female S-D (Sprague-Dawley) rat, three large studies were performed: experiment 1, tumorigenesis in rats fed AIN-76A diet and given 25 mg/kg DMBA and 1.25 or 2.5% whole tea extract or water to drink; experiment 2, tumorigenesis in rats given 15 mg/kg DMBA and the same diet and fluids as in experiment 1; experiment 3, tumorigenesis in rats fed control or HF (high fat, corn oil) diet and given 15 mg/kg DMBA and 2% tea or water to drink. Tea was given throughout the experiment; DMBA was given by gastric gavage at 8 weeks of age. There was no consistent effect of tea on tumorigenesis in rats fed AIN-76A diet; there was, however, evidence in experiment 3 of a reduction of tumorigenesis by tea in rats fed the HF diet. In experiment 3, rats fed the HF diet and given water showed the expected increase in tumor burden (number and weight) compared with rats fed control diet. However, rats fed the HF diet and given 2% tea showed no increase in tumor burden; their tumor burden was significantly lower than in rats fed the HF diet and given water (P < 0.01) and was not different from rats fed control diet and given water or tea. In addition, in experiment 3, the number of malignant tumors per tumor- bearing rat was increased by the HF diet in water-drinking rats (P < 0.01) but not in tea-drinking rats. Therefore, it appears that tea partially blocked the promotion of DMBA-induced mammary tumorigenesis by the HF diet.      

Prevention of colonic aberrant crypt foci and modulation of large bowel microbial activity by dietary coffee fiber, inulin and pectin

The present experiments were aimed at developing novel dietary fibers to aid in reduction of colon cancer risk. We assessed the effects of coffee (non-fiber fraction), coffee fiber (arabino-galactose polymer) and inulin (oligo-fructose) in male F344 rats using formation of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in the colon as the measure of preventive efficacy (or lack of such). At 5 weeks of age, groups of rats were fed the AIN-76A (control) and experimental diets that contained 1% coffee, 10% coffee fiber, 10% inulin, 10% pectin (positive control for fiber) or 200 p.p.m. piroxicam (a known ACF inhibitor). At 7 weeks of age, all animals were s.c injected with AOM (15 mg/kg body wt) once weekly for 2 weeks. All rats were killed 8 weeks after the last AOM injection and ACF were counted. The contents of the cecum were analyzed for bacterial beta-glucuronidase activity and short-chain fatty acids (SCFAs). Dietary administration of coffee fiber significantly suppressed AOM-induction of colonic ACF, in terms of total number, as well as crypt multiplicity and number of ACF/cm2 colon (P < 0.01-0.001). Inulin diet had no significant effect on total ACF, but had reduced the number of ACF/cm2 (P < 0.05). Whereas coffee had no effect on ACF formation, 10% pectin diet and 200 p.p.m. piroxicam significantly suppressed colonic ACF (P < 0.001) as had been expected. A significant reduction of cecal beta-glucuronidase activity was observed in the rats fed coffee, coffee fiber and pectin diets. Further, coffee fiber, inulin and pectin increased cecal SCFA levels 3- to 5-fold. These results suggest that coffee fiber can prevent colon cancer risk. Further studies are warranted to determine the full potential of this fiber in pre-clinical efficacy studies.      

A rapid dual organ rat carcinogenesis bioassay for evaluating the chemoprevention of breast and colon cancer

In this study we evaluated the effect of dietary administration of a high fat, low fiber diet (HRD) with or without 2% phytic acid (PA) on the development of mammary cancer and/or colon cancer in rats exposed to methylnitrosourea (MNU), azoxymethane (AOM) or MNU + AOM. The rats were fed a HRD alone or a HRD + 2% PA. At the end of week 2, the rats were given either a s.c. injection of MNU (50 mg/kg body wt) or one of normal saline (vehicle). At the end of weeks 3 and 4, the rats were given either a s.c. injection of AOM (15 mg/kg body wt per week) or one of normal saline (vehicle). Nine weeks after the injection of MNU or saline, 10 rats from each group were sacrificed and the mammary tumor incidence and the number of colonic aberrant crypt foci (ACF) were compared between different groups. The administration of different diets was continued for an additional 21 weeks and the mammary tumor and colon tumor incidence between different groups were compared. Results showed that rats injected with MNU alone did not develop ACF or colon tumors while those injected with AOM alone did not develop mammary tumors. Linear regression analysis of the number of ACF at 11 weeks versus colonic tumor incidence at 32 weeks, and the linear regression analysis of mammary tumor incidence at 11 weeks versus mammary tumor incidence at 32 weeks, both showed good linear correlation. These results demonstrate the potential value of the short term dual organ carcinogenesis bioassay for screening chemopreventive agents for their relative ability to inhibit the development of mammary cancer and/or colon cancer while on high risk diet.     

Preventive potential of wheat bran fractions against experimental colon carcinogenesis: implications for human colon cancer prevention

Epidemiological studies suggest an inverse relationship between the intake of dietary fiber, particularly fiber from cereal grains, and colon cancer risk. Animal model assays have demonstrated that the protective effects of dietary fiber on colon cancer development depend on the nature and source of the fiber. Wheat bran (WB) appears to inhibit colon tumorigenesis more consistently than do oat bran or corn bran. This study was designed to determine whether specific WB fractions such as WB fiber, WB lipids, or phytic acid differentially affect colon carcinogenesis in a well-established colon cancer model. In addition, the modulating effect of specific fractions of WB on the activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-1 and COX-2 enzymes were assessed in colon tumors as those have been shown to play a role in tumor progression. At 5 weeks of age, groups of male F344 rats were assigned to one of six diets: a high-fat diet containing 10% WB (control diet) and experimental high-fat diets containing 10% dephytinized WB (WB-P), 10% defatted WB (WB-F), 10% dephytinized and defatted WB (WB-PF), 10% WB-PF fortified with 2% bran oil and/or with 0.4% phytate. At 7 weeks of age, all eats except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight/week. They continued to receive their respective diets until 50 weeks after carcinogen treatment and were then killed. Colon tumors were analyzed for iNOS, COX-1, and COX-2 expression and enzymatic activities. Colon tumors were evaluated histopathologically and classified as adenomas and adenocarcinomas. We found that removal of phytic acid (WB-P) or lipids (WB-F) from WB had no significant effect on colon tumor incidence (% animals with tumors) or multiplicity (tumors/ animal), whereas removal of both phytate and lipids from WB (WB-PF) significantly increased colon tumor multiplicity and volume. Interestingly, WB-PF fortified with excess bran oil or with bran oil plus phytate significantly inhibited colon tumor incidence, multiplicity, and volume; but supplementation of WB-PF with phytate alone had no significant effect on colon tumorigenesis in rats suggesting that lipid fraction of WB possesses tumor-inhibitory properties. Moreover, feeding WB-PF diet significantly increased iNOS, total COX and COX-2 enzyme activities, and iNOS protein expression in colon tumors as compared with wheat bran control diet. Feeding the WB-PF that was fortified with excess bran oil alone or with bran oil plus phytate significantly suppressed the activities of iNOS and COX-2 as well as the expression of iNOS and COX-2 in colon tumors compared with that in rats fed the WB diet or WB-PF diet. The study demonstrates for the first time that the lipid fraction of wheat bran has strong colon tumor inhibitor properties. The exact mechanism(s) by which the lipid fraction of WB inhibits colon carcinogenesis in addition to alteration of iNOS and COX activities remains to be elucidated. Additional studies are warranted to identify biologically active constituents of lipid fraction of WB and their relative role in colon tumor inhibition.     

Nutrition and diet in the development of gastrointestinal cancer

Diet plays a role in the prevention and development of gastrointestinal cancers. The majority of available research consists of case-control studies, but the number of clinical trials is growing. The dietary recommendations to reduce gastrointestinal cancer risk include lowering total energy, fat, and saturated fat intake; avoidance of grilled and smoked foods; avoidance of alcohol; and increasing intake of fruits, vegetables, and fiber. Studies of esophageal cancer support these dietary approaches, with the exception of dietary fat reduction and increased green tea intake. For gastric cancer, consuming additional fruits and vegetables, including those high in ascorbic acid, may reduce risk, and the capacity for diet to alter Helicobacter pylori infection should be explored. Recent interventional trials do not support a role for high-fiber or low-fat diets in reducing development of colon adenomas, although the evidence does not rule out efficacy at earlier stages of disease. Finally, the evidence for a relationship between pancreatic cancer and diet remains sparse and warrants additional investigation.     

Development of a rat model by 3,4-benzopyrene intra-pulmonary injection and evaluation of the effect of green tea drinking on p53 and bcl-2 expression in lung carcinoma

Background A convenient animal model of primary lung cancer is compelling for investigation into the disease mechanisms and for development of therapeutic strategies. This study aims to develop a reproducible rat model for lung carcinoma by intra-pulmonary injection of 3,4-benzopyrene, and to evaluate the preventive effect of green tea on the formation of lung carcinoma. Methods Sprague–Dawley rats of the same ages were randomly assigned into three groups treated differently. Rats in group one were given green tea in drinking water (tea concentration: 1.2%; tea polyphenols in the tea solution: 0.3%); rats in the groups two and three were given blank drinking water. Rats in the groups one and two were injected intra-pulmonarily with 3,4-benzopyrene dissolved in corn oil (2 mg/0.2 mL/injection, fortnightly, 4 times in all); rats in the group three were injected with the vehicle corn oil as the control for injection. All the rats were sacrificed one year after the first intra-pulmonary injection. Tumors developed in rats and lung tissues were collected for carcinoma diagnosis and for p53 and bcl-2 expression. Results Intra-pulmonary injection of 3,4-benzopyrene steady induced lung carcinoma at a success rate of 75%. Administration with green tea drinking significantly reduced the incidence of lung carcinoma to 30%. Green tea up-regulated p53 expression in lung carcinoma, but significantly down-regulated bcl-2 expression. Conclusions Intra-pulmonary injection of 3,4-benzopyrene can steady induce lung carcinoma in rats, and green tea has preventive effect against lung cancer possibly by regulating expression of some critical genes such as p53 and bcl-2.     

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION: Protection by green tea, black tea, and indole-3-carbinol against 2-amino-3-methylimidazo[4,5-f]quinoline-induced DNA adducts and colonic aberrant crypts in the F344 rat

Male F344 rats were exposed for 8 weeks to extracts of greentea (2% w/v) or black tea (1% w/v), or to 0.1% dietary indole-3-carbinol(I3C). In weeks 3 and 4 of the study, rats were given 2-amino-3-methylimidazo[4,5-f]-quinoline (IQ) every other day by oral gavage (50 mg/kgbody wt) in order to induce aberrant crypt foci (ACF) in thecolon. Compared with controls given IQ alone, all three inhibitorsreduced the number of total aberrant crypts per colon, and greentea and I3C inhibited significantly the mean number of ACF (P< 0.05). Rats pre-treated with green tea, black tea, or I3Cand given a single p.o. injection of 50 mg IQ/kg body wt 24–48h before sacrifice had reduced levels of IQ-DNA adducts in theliver, and excreted lower amounts of IQ and other promutagensin the urine and feces. Inhibitors also reduced the excretionof IQ-sulfamate in the urine, but increased the relative amountsof IQ-5-O-sulfate and IQ-5-O-glucuronide. Western blotting togetherwith assays for 7-ethoxyresorufin O-deethylase and methoxyresorufinO-demethylase established that I3C preferentially induced cytochromeP4501A1 over 1A2, consistent with the altered profile of urinarymetabolites. However, both teas caused slight induction of cytochromeP4501A2 versus 1A1, which would be predicted to enhance theactivation of IQ. Thus, green tea and black tea are likely toprotect against IQ-DNA adducts and ACF by mechanisms other thaninduction of cytochromes P450, such as inhibition of enzymeswhich activate IQ or the scavenging of reactive intermediates.     

Green tea catechins enhance tumor development in the colon without effects in the lung or thyroid after pretreatment with 1,2-Dimethylhydrazine or 2,2'-dihydroxy-di-n-propylnitrosamine in male F344 rats

Modifying effects of green tea catechins (GTCs) on the post-initiation stage of colon, lung and thyroid carcinogenesis were examined in F344 male rats. Groups of 20 animals were given subcutaneous injections of 40 mg/kg body wt of 1,2-dimethylhydrazine twice a week for 2 weeks or oral administration of 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) in the drinking water for 2 weeks for initiation. They then received diet containing 1 or 0.1% green tea catechin or basal diet alone for 33 weeks. Histopathological examination after final sacrifice showed that although total incidence and multiplicity of colon tumors were not significantly different from controls, values for colon adenomas were decreased while those for carcinomas and the average size of tumors were significantly increased in the 0.1% GTC group. A similar tendency was observed for the 1% GTC group. Incidences and/or multiplicity of lung hyperplasia and tumors, and thyroid lesions did not significantly vary among the DHPN-treated groups. These results indicate that GTCs do not inhibit, but rather may enhance colon carcinogenesis, while not influencing lung and thyroid carcinogenesis under the present experimental conditions.     

Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study

The relationships between green tea and black tea consumption and colorectal cancer risk were examined within the Singapore Chinese Health Study, a prospective cohort study of diet and cancer involving >60,000 men and women. Intake of green tea and black tea was assessed through in-person interviews. Incident cancer cases and deaths among cohort members were identified through record linkage of the cohort database with respective databases from the nationwide Singapore Cancer Registry and the Singapore Registry of Births and Deaths. The proportional hazard regression method was used to examine the associations between intake of green and black tea separately and colorectal cancer risk with adjustment for potential confounders. After an average of 8.9 years of follow-up, 845 colorectal cancer cases were identified. Subjects who drank green tea exhibited a statistically non-significant increase in risk [relative risk (RR) = 1.12, 95% confidence interval (CI) = 0.97-1.29] relative to non-drinkers of green tea. This risk increase was mainly confined to men (RR = 1.31, 95% CI = 1.08-1.58); the comparable RR in women was 0.89 (95% CI = 0.71-1.12). In men, the green tea-colorectal cancer association was noted mainly in those with advanced disease (Duke C or D) (RR = 1.53, 95% CI = 1.19-1.97), and the association was dose dependent (P for trend = 0.0002). This latter association was especially strong within the colon subsite (RR = 1.75, 95% CI = 1.24-2.46; P for trend < 0.0001). Irrespective of gender, intake of black tea was not associated with risk of colorectal cancer (RR = 0.92, 95% CI = 0.79-1.07) in this Asian population.     

Dietary whey protein protects against azoxymethane-induced colon tumors in male rats.

Epidemiological studies have suggested a relationship between diet and colon cancer incidence. Results from animal studies suggest that whey protein, but not casein protein, may provide protective effects against experimentally induced breast cancer in animals. In the current study, we investigated the effects of casein and whey diets on chemically induced colon cancer in male rats. Pregnant female Sprague Dawley rats (days 3-4 of gestation) were maintained on modified AIN-93G diets formulated with a single protein source of either casein or whey. Life-time exposure to these diets was studied in the F1 generation (experiment A) or the F2 generation (experiment B). Male offspring were weaned to the same diets as the dams and were maintained on these diets throughout the study. At age 90 days, all rats received azoxymethane once a week for 2 weeks (s.c., 15 mg/kg). Forty weeks after the last azoxymethane injection, all rats were euthanized, the colon was examined visually for tumors, and each tumor was histologically evaluated. The weights and distribution of all of the tumors were recorded. In experiment A, rats fed the casein diet had a 56% incidence of colon tumors compared with 30% of the rats on whey-based diets (P < 0.05). In experiment B, rats fed the casein diet had 50% incidence of colon tumors compared with 29% in the whey group (P < 0.05). There were no significant effects of diet on tumor multiplicity or mass. These results suggest that consumption of whey protein-containing diets may reduce the risk of developing colon tumors.     

Reliability of a short-term test for hepatocarcinogenesis induced by aflatoxin B1.

The reliability of a short-term test for hepatocarcinogenesis induced by aflatoxin B1 (AFB1) was tested by comparing the early appearance of gamma-glutamyl transpeptidase (GGT)-positive foci with the occurrence of primary liver cancer at a later stage. All rats received a basic short-term treatment with AFB1 intraperitoneally, during which three experimental groups received Chinese green tea or 2000 or 5000 ppm butylated hydroxyanisole in the diet and a control group received basic diet. Some of the rats in each group were sacrificed at the end of the short-term procedure, and the remainder were observed up to 92 weeks. The livers of all animals were examined for GGT-positive foci or primary liver tumours. The GGT-positive foci were most numerous and largest and the incidence of liver tumours was highest in the control group. These findings suggest that GGT-positive foci are a valuable preneoplastic marker for AFB1-induced hepatocarcinogenesis, that the short-term model is fairly reliable, and that both Chinese green tea and butylated hydroxyanisole inhibit AFB1-induced hepatocarcinogenesis.     

Green tea, black tea and colorectal cancer risk: a meta-analysis of epidemiologic studies

Experimental studies have supported tea as a chemopreventive agent for colorectal cancer. No quantitative summary of the epidemiologic evidence on tea and colorectal cancer risk has ever been performed. The current meta-analysis included 25 papers conducted in 11 countries across three continents (North America, Asia and Europe). Summary odds ratios (ORs) for highest versus non/lowest tea consumption levels were calculated based on fixed and random effects models. The meta-regression and stratified methods were used to examine heterogeneity across studies. For green tea, the combined results from eight studies indicated a reduced risk of colorectal cancer with intake [summary OR = 0.82, 95% confidence interval (CI) = 0.69-0.98]. The protective effect is mainly found among the three case-control studies of colon cancer (summary OR = 0.74, 95% CI = 0.60-0.93). Results from studies of rectal cancer irrespective of study design (case-control versus cohort) (summary OR = 0.99, 95% CI = 0.71-1.37) and cohort studies of colon cancer (summary OR = 0.99, 95% CI = 0.79-1.24) were compatible with the null hypothesis. For black tea, the summary OR derived from 20 studies was 0.99 (95% CI = 0.87-1.13). There is wide divergence in results across the 20 individual studies; formal tests for homogeneity across studies revealed statistically significant differences in findings across all studies (P < 0.001), amongst the 7 cohort studies (P = 0.002), and amongst the 13 case-control studies (P < 0.001). Despite the strong evidence from in vitro and non-human in vivo studies in support of green and black tea as potential chemopreventive agents against colorectal cancer, available epidemiologic data are insufficient to conclude that either tea type may protect against colorectal cancer in humans.     

A Very Low Dose of Green Tea Polyphenols in Drinking Water Prevents N-Methyl-N-nitrosourea-induced Colon Carcinogenesis in F344 Rats

The effect of tea polyphenols, major constituents of tea, on colon carcinogenesis was investigated. A total of 129 female F344 rats were given an intrarectal instillation of 2 mg of N-methyl-N-nitrosourea 3 times a week for 2 weeks, and received a water solution of green tea extract (GTE) as drinking water throughout the experiment. Autopsies at week 35 revealed significantly lower incidence of colon carcinomas in rats ingesting 0.05%, 0.01% or 0.002% GTE solution than in controls ingesting 0% GTE solution: 43%, 40% and 33% vs. 67%. The data suggest that GTE, even at a very low dose (0.002% solution), has a potent inhibitory effect on colon carcinogenesis.     

Prevention of colon cancer by low doses of celecoxib, a cyclooxygenase inhibitor, administered in diet rich in omega-3 polyunsaturated fatty acids

Epidemiologic and animal studies suggest that a high-fat diet containing mixed lipids promotes colorectal cancer, whereas fish oil lacks promoting effect. Although cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colon carcinogenesis, administration of high doses of these agents over time may induce side effects. Here, we compared the efficacy of moderately high and low doses of celecoxib administered in diets high in mixed lipids (HFML) or fish oil (HFFO) against azoxymethane-induced colon carcinogenesis in male F344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight once weekly for 2 weeks), groups of rats were fed the HFML and HFFO diets containing 0, 250, 500, and 1,000 ppm celecoxib. Rats were killed 26 weeks later and colon tumors were subjected to histopathologic examination and analyzed for total COX and COX-2 synthetic activities and COX-2 expression. Rats fed the HFFO diet showed significantly lower colon tumor incidence and multiplicity compared with rats fed the HFML diet. Celecoxib at 250, 500, and 1,000 ppm in either diet significantly suppressed colon carcinogenesis. Inhibition of colon adenocarcinomas were more pronounced in animals given 250 ppm celecoxib in HFFO diet compared with 250 ppm celecoxib given in HFML diet, suggesting some synergism between omega-3 polyunsaturated fatty acids (PUFA) and celecoxib. Inhibition of colon tumors by celecoxib was associated with lower levels of COX-2 activity and expression in colon tumors. These studies support the use of low doses of celecoxib in omega-3 PUFA-rich diet as a promising approach for clinical trials.     

Mechanisms in the chemoprevention of colon cancer: modulation of protein kinase C, tyrosine protein kinase and diacylglycerol kinase activities by 1,4-phenylenebis-(methylene)selenocyanate and impact of low-fat diet

Epidemiological and experimental studies suggest an inverse relationship between the intake of dietary selenium and/or low fat-intake and colon cancer risk. Efficacy studies in rodents suggest that the organoselenium compound 1, 4-phenylenebis(methylene)selenocyanate (p-XSC), is a more effective and less toxic chemopreventive agent than other organic or inorganic selenium compounds such as selenomethionine and Na2SeO3. The efficacy of p-XSC against colon cancer is significantly augmented by a low-fat diet. To explore the mechanisms by which this combined inhibiting effect against colon carcinogenesis comes about, we have investigated protein kinase C (PKC), tyrosine protein kinase (TPK), diacylglycerol kinase (DGK) activities and 8-isoprostane levels in colonic mucosa and tumor tissues in an azoxymethane (AOM)-induced rat colon cancer model. Weanling male F344 rats were fed the semipurified AIN-76A diet until seven weeks of age. Then various experimental groups were fed the low- or high-fat diets containing 0 or 20 ppm p-XSC (10 ppm as selenium). At seven weeks of age, groups of rats were injected s.c. with azoxymethane (AOM; 15 mg/kg body wt., once weekly for 2 weeks) and continued on their respective experimental diets until 38 weeks after the second AOM treatment. They were then sacrificed and colonic mucosal and tumor samples were evaluated for PKC, TPK, DGK and 8-isoprostane levels. Administration of p-XSC along with a low-fat diet significantly inhibited Ca+2-dependent and -independent PKC (P<0.05-0.01) activities in colonic mucosa and tumors. Administration of p-XSC either low-fat or high-fat diet significantly suppressed both colonic mucosal and tumor TPK activity (P<0.05-0.01). Suppression of TPK activity was more pronounced in rats maintained on a low-fat diet containing p-XSC. In contrast, rats receiving p-XSC with either low- or high fat diet showed significantly increased DGK activity (P<0.01-0.0001). Rats fed low-fat or high-fat plus p-XSC had lower-levels of 8-isoprostane in the colonic tumors than animals who had been given low- or high-fat diets without the organoselenium compound. Interestingly, 8-isoprostane levels were lower in the colon tumors of the rats fed the low-fat diet than those fed the high-fat diet. Our findings suggest that p-XSC induced down-regulation of PKC and TPK activities and up-regulation of DGK activity. These events may in part be responsible for the chemopreventive activity against colon carcinogenesis. Further, this study implies that p-XSC with a low-fat dietary regimen will augment regulation of PKC, TPK and DGK activities in the colon.     

Promotion of colon carcinogenesis through increasing lipid peroxidation induced in rats by a high cholesterol diet

To examine the influence of hypercholesteremia on 1,2-dimethylhydrazine (DMH)-induced rat colon cancer, Sprague-Dawley rats received dietary cholesterol (CH, 0–2%) and cholic acid (CA, 0.25%) with or without DMH (20 mg/kg, s.c. injection) for 18 weeks. The rats receiving dietary cholesterol and cholic acid all significantly increased total serum cholesterol and lipids but only a high cholesterol diet (2% CH plus 0.25% CA) decreased the activity of glutathione peroxidase (GSH-Px) and increased the formation of peroxides in the colon (P < 0.01). The rats that received the combination of DMH and high cholesterol diet enhanced these effects. At the end of the experiment, the diet group administered DMH and high cholesterol (2% CH plus 0.25% CA) developed colon adenoma at 50% of incidence in pathological examination, but no colon adenoma formed in the rats treated with high cholesterol alone. It is supposed that a non-carcinogenic agent like cholesterol may potentiate the carcinogenicity of DMH in rats via an increase of lipid peroxidation and decrease in the activity of peroxidase in the target organ.     

Soy protein isolate consumption protects against azoxymethane-induced colon tumors in male rats

Male Sprague-Dawley rats (F2 generation) that had been fed modified American Institute of Nutrition-93G diets formulated with a single protein source of either casein or soy protein isolate for their entire life received azoxymethane once a week for 2 weeks (s.c., 15 mg/kg) starting at age 90 days. Forty weeks later, all rats were euthanized, the colon was examined visually for masses and these were subsequently evaluated histologically. Rats fed the casein diet had a 50% incidence of colon tumors compared with 12% on soy protein-based diets (P<0.05). These results suggest that consumption of soy protein-containing diets may reduce the risk of developing colon tumors.     

Influence of diets containing high and low risk factors for colon cancer on early stages of carcinogenesis in human flora-associated (HFA) rats

Germ-free rats colonised with a human intestinal flora were fed diets containing high risk (HR) or low risk (LR) factors for colorectal cancer, and putative biomarkers were evaluated in the colonic mucosa; (i) proliferation, (ii) 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci and (iii) DMH-induced DNA damage. The HR diet was high in fat (45% of calories) and low in calcium and fibre, reflecting levels characteristic of typical western diets. The LR diet was low in fat (<5% of calories), and high in calcium and fibre. The nutrient/energy ratio of the two diets were similar. Mucosal crypt cell proliferation, assessed after microdissection, was higher on the LR diet (mean number of mitoses per crypt was 2.65 on the LR diet, and 1.62 on the HR diet; P < 0.05). Aberrant crypt foci (ACF) were assessed in the mucosa 12 weeks after DMH treatment. On the HR diet there were significantly more small ACF with 1 and 2 crypts per focus, but fewer ACF with 3, 5 and 7 or more crypts per focus. There was no significant difference in total ACF or the total number of crypts. The effect of diet on DNA damage in the colon was assessed in vivo by the comet assay. Animals were fed a HR or LR diet for 12 weeks before treatment with DMH or saline. For carcinogen-treated animals, DNA damage was significantly higher in colon cells from animals on the HR diet. On the LR diet both DNA damage and the induction of small ACF were reduced despite an increase in cell proliferation. The increase in large ACF on the LR diet may be attributable to elevated crypt cell proliferation possibly increasing crypt fission rates.      

Green tea consumption and the risk of pancreatic and colorectal cancers

The effect of green tea drinking in reducing human cancer risk is unclear, though a protective effect has been reported in numerous animal studies and several epidemiologic investigations. Herein the hypothesis that green tea consumption may reduce the risk of cancers of the colon, rectum and pancreas is examined in a large population-based case-control study conducted in Shanghai, China. Newly diagnosed cancer cases (931 colon, 884 rectum and 451 pancreas) during 1990–1993 among residents 30–74 years of age were included. Controls (n = 1,552) were selected among Shanghai residents and frequency-matched to cases by gender and age. Multivariate odds ratios (ORs) and 95% confidence intervals (Cls) of each cancer associated with green tea consumption were derived after adjustment for age, income, education and cigarette smoking. Additional adjustment for dietary items and body size was found to have minimal impact. An inverse association with each cancer was observed with increasing amount of green tea consumption, with the strongest trends for rectal and pancreatic cancers. For men, compared with non-regular tea drinkers, ORs among those in the highest tea consumption category (≥300 g/month) were 0.82 for colon cancer, 0.72 for rectal cancer and 0.63 for pancreatic cancer, with p values for trend being 0.38, 0.04 and 0.04, respectively. For women, the respective ORs for the highest consumption category (≥200 g/month) were 0.67, 0.57 and 0.53, with the respective p values for trend being 0.07, 0.001 and 0.008. Our findings provide further evidence that green tea drinking may lower the risk of colorectal and pancreatic cancers. Int. J. Cancer, 70:255–258, 1997. © 1997 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.