Studies on the mechanism of cancer protection by wheat bran: effects on the absorption, metabolism and excretion of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)

We examined ways in which dietary supplements of wheat bran may protect against colon cancer. The effects of supplementing the diet of female Wistar rats with 10% wheat bran on the disposition and metabolism of the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) labelled with (14)C was determined. Our data show that the wheat bran had a major effect on both the distribution and metabolism of IQ. At a low dose of IQ (1 mg/kg), we unexpectedly found that up to 2 h after gavage there were higher concentrations of radioactivity in the plasma of rats fed wheat bran compared with the controls, but there were lower concentrations of radioactivity after 2 h. At a high dose of IQ (50 mg/kg), there were always lower concentrations of radioactivity in the plasma of rats fed wheat bran compared with the control rats. One of the most marked effects of wheat bran was apparently to significantly retard the metabolism of IQ in the plasma when this was fed at either dose. There were also differences between the rats fed wheat bran and the control in the concentrations and types of IQ metabolites in the urine.     

Effects of resistant starch and nonstarch polysaccharides on colonic luminal environment and genotoxin-induced apoptosis in the rat

Fermentation of polysaccharides in the colon seems likely to regulate tumorigenesis but the mechanisms are unclear. A possible mechanism may be through facilitation of the acute apoptotic response to genotoxin-induced DNA damage. This study evaluated the effects of selected dietary polysaccharides, resistant starch (supplied as Hi-maize) and nonstarch polysaccharides (supplied as wheat bran and cellulose) on certain biological events relevant to protection against colon cancer (fecal bulk, pH, butyrate and apoptosis). Male Sprague-Dawley rats were fed the different experimental diets for a period of 4 weeks, after which a single azoxymethane injection was given to induce DNA damage; 6 h later the acute apoptotic response was measured. Other measures included short chain fatty acid (SCFA) levels, fecal bulk and pH. All wheat bran treatments significantly (P < 0.05) enhanced carcinogen-induced apoptosis in the distal colon, increased fecal bulk and butyrate levels and reduced fecal pH, when compared with rats fed NF or Cellulose diets. Total SCFA (P < 0.001, r = 0.496) and butyrate levels (P < 0.001, r = 0.353) in the feces correlated positively with the acute apoptotic response in distal colonic crypts. Resistant starch supplementation by this modest amount did not enhance carcinogen-induced apoptosis. While it did significantly increase bulk, SCFA and butyrate levels and lower pH, the magnitude of these effects was not as great as with wheat bran. These findings indicate that wheat bran is the most effective regulator of these biological events of relevance to protection against colon cancer. Assuming that the acute apoptotic response to genotoxic carcinogens acts to remove genetically damaged cells that might otherwise form mutated clones that progress to malignancy, we have identified an additional biological mechanism by which dietary polysaccharides provide protection.     

The effect of flaxseed and wheat bran consumption on urinary estrogen metabolites in premenopausal women.

Estrogen is metabolized along two competing pathways to form the 2-hydroxylated and the 16alpha-hydroxylated metabolites. Based on proposed differences in biological activities, the ratio of these metabolites, 2-hydroxyestrogen:16alpha-hydroxyestrone (2:16alpha-OHE1), has been used as a biomarker for breast cancer risk. Women with an elevated 2:16alpha-OHE1 ratio are hypothesized to be at a decreased risk of breast cancer. Flaxseed, the most significant source of plant lignans, and wheat bran, an excellent source of dietary fiber, have both been shown to have chemoprotective benefits. Some of these benefits may be attributable to their influence on endogenous sex hormone production and metabolism. We examined the effect of flaxseed consumption alone and in combination with wheat bran on urinary estrogen metabolites in premenopausal women. Sixteen premenopausal women were studied for four feeding treatments lasting two menstrual cycles each in a randomized cross-over design. During the four feeding treatments, subjects consumed their usual diets supplemented with baked goods containing no flaxseed or wheat bran, 10 g of flaxseed, 28 g of wheat bran, or 10 g of flaxseed plus 28 g of wheat bran/day. Urinary excretion of 2-hydroxyestrogen and 16alpha-hydroxyestrone, as well as their ratio, 2:16alpha-OHE1, were measured by enzyme immunoassay. Flaxseed supplementation significantly increased the urinary 2:16alpha-OHE1 ratio (P = 0.034), but wheat bran had no effect. These results suggest that flaxseed may be chemoprotective in premenopausal women.     

Randomized trial of dietary fiber and Lactobacillus casei administration for prevention of colorectal tumors

The epidemiologic evidence that dietary fiber protects against colorectal cancer is equivocal. No large-scale clinical study of the administration of Lactobacillus casei has been reported. We examined whether dietary fiber and L. casei prevented the occurrence of colorectal tumors. Subjects were 398 men and women presently free from tumor who had had at least 2 colorectal tumors removed. Subjects were randomly assigned to 4 groups administered wheat bran, L. casei, both or neither. The primary end point was the presence or absence of new colorectal tumor(s) diagnosed by colonoscopy after 2 and 4 years. Among 380 subjects who completed the study, 95, 96, 96 and 93 were assigned to the wheat bran, L. casei, both and no treatment groups, respectively. Multivariate adjusted ORs for occurrence of tumors were 1.31 (95% CI 0.87-1.98) in the wheat bran group and 0.76 (0.50-1.15) in the L. casei group compared to the control group. There was a significantly higher number of large tumors after 4 years in the wheat bran group. The occurrence rate of tumors with a grade of moderate atypia or higher was significantly lower in the group administered L. casei. No significant difference in the development of new colorectal tumors was observed with administration of either wheat bran or L. casei. However, our results suggest that L. casei prevented atypia of colorectal tumors.     

Carcinogen binding to various types of dietary fiber

The percent of the carcinogen 1,2-dimethylhydrazine (DMH) bound to a variety of fibers, such as wheat bran, corn bran, citrus pulp, citrus pectin, and alfalfa, was examined at pH values ranging from 1 to 12. The percent of DMH bound to wheat bran increased from 4% at PH 1 to 55% at pH 2 to 77% at pH 12. A sharp rise in carcinogen binding to corn bran occurred between pH 5% of the DMH was bound and pH 8 where 51% of the DMH was bound. The percent of DMH bound to dehydrated citrus pulp also increased as the pH increased with 10% binding observed at pH 1 and with 57% binding observed at pH 12. Between pH 2 and pH 7, the percent of DMH bound to pectin decreased from 60 to 11%. As the pH became more basic, the percent of DMH bound to pectin increased to 42% at pH 12. The sharpest rise in the percent of DMH bound to alfalfa meal occurred between pH 10.5 and pH 12.0. Results from this experiment showed that the affinity to various types of dietary fibers for the colon carcinogen DMH was differentially affected by pH. These results suggested that the protective effect of certain types of dietary fiber against chemically induced colon cancer my in part be attributed to enhanced carcinogen binding by dietary fiber in the colon.     

Interventional trial for colorectal cancer prevention in Osaka

We established a protocol for an interventional randomized controlled trial for the prevention of colorectal tumors, in which special importance was attached to practicality. The subjects are patients with multiple colorectal tumors, who form a high risk group for colorectal cancer. Two regimens were formulated for the prevention of colorectal cancer. One was dietary guidance alone (Regimen I), and the other was dietary guidance plus the ingestion of wheat bran biscuits (Regimen II). One of the two regimens is assigned at random each week in advance, and the patients are recruited to receive the regimen of the week in which they are first examined, after giving informed consent. The dietary guidance aims to restrict the energy intake of oil and fat to 18-22% of the total energy intake. Biscuits with a wheat bran content of 30% by weight, which we developed, were prescribed at 25 g/day (7.5 g/day as wheat bran). The main end points of the trial were examinations for recurrence of colorectal tumors after 4 years. The target number of patients is 200 in total, i.e., 100 for each group. The recruiting of subjects was started in June, 1993, and finished in September, 1997; 100 (90%) of 115 patients recruited for Regimen I and 100 (88%) of 116 patients recruited for Regimen II consented to participate in the trial. No severe adverse effects have been reported, and the trial is progressing well. The trial will be completed in September, 2001, when the 4-year follow-up of the last patient will end.     

Effects of dietary wheat bran fiber on rectal epithelial cell proliferation in patients with resection for colorectal cancers

A preponderance of carcinogenesis studies in rodents and epidemiologic studies in humans suggests a potential role of dietary fiber in the prevention of colorectal cancer. Recently, wheat bran fiber used as a dietary supplement has been shown to decrease the growth of rectal adenomatous polyps in patients with familial polyposis; however, few studies of high-risk human populations have been attempted to determine the effects of dietary fiber supplementation on markers of carcinogenesis in the colon or rectum. We have designed a one-arm study to evaluate the effects of dietary supplementation with wheat bran fiber [i.e., 13.5 g/day for 8 wk; after 1 mo, 2 g/day (compliance evaluation period)] on [3H]thymidine rectal mucosa cell labeling (i.e., percent of epithelial cells incorporating [3H]thymidine into DNA in intact rectal crypt cells over a 90-min exposure as well as in minced rectal biopsy tissue over a 24-hr exposure) in rectal biopsy specimens. The biopsy specimens were obtained at sigmoidoscopy in 17 compliant patients with a history of resected colon or rectal cancer. We categorized patients as having initially low or initially high [3H]thymidine-labeling indices (i.e., percent of mucosa cells that incorporate [3H]thymidine into DNA during 1.5- or 24-hour in vitro incubations) by using the median baseline labeling index as a cutoff between high and low values. On the basis of a chi-square test used to identify patients with a statistically significant (P less than .001) change, six of the eight patients who initially had high 24-hour outgrowth labeling indices showed a significant decrease in the rectal mucosa biopsy specimens obtained after treatment. An overall 22% decrease was observed in rectal mucosa cell biopsy specimens obtained at study termination (P less than .001). Of the eight patients with initially high total [3H]thymidine-labeling indices in crypt organ culture, four had a significant (P less than .001) decrease from baseline values, one had a significant increase, and three showed no change following the fiber intervention. The wheat bran fiber dietary supplement of 13.5 g/day was well tolerated by this group of older (54-70 yr) patients. Although the [3H]-thymidine labeling index data suggest that the wheat bran fiber supplement can inhibit DNA synthesis and rectal mucosa cell proliferation in high-risk patients, the results of this small pilot study should not be overinterpreted vis à vis the potential role of wheat bran fiber as a chemopreventive agent for colorectal cancer.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of dietary wheat bran and dehydrated citrus fiber on 3,2'-dimethyl-4-aminobiphenyl-induced intestinal carcinogenesis in F344 rats

The effect of dietary wheat bran and dehydrated citrus fiberon 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced colon and smallintestinal carcinogenesis was studied in male F344 rats. Weanlingrats were fed semipurified diets containing 5% alphacel, 5%alphacel + 15% wheat bran or 5% alphacel + 15% citrus fiber.At 7 weeks of age, all animals, except vehicle-treated controls,received weekly s.c. injections of 50 mg DMAB/kg body weightfor 20 weeks. The DMAB- or vehicle-treated groups were autopsied20 weeks after the last injection of DMAB. The animals fed thewheat bran diet and treated with DMAB had a lower incidence(number of animals with tumors) and multiplicity (number oftumors/tumor-bearing animal) of colon and small intestinal tumorsthan did those fed the control diet and treated with DMAB. Animalsfed the diet containing citrus fiber developed fewer small intestinaltumors (incidence and multiplicity) than did the rats fed thecontrol diet; the number of adenocarcinomas was reduced in ratsfed the citrus fiber diet. This study thus indicates that dietscontaining wheat bran and citrus fiber reduce the risk for DMAB-inducedintestinal cancer and that the protection against colon cancerdepends on the type of fiber.     

Effect of dietary fiber on the induction of colorectal tumors and fecal beta-glucuronidase activity in the rat.

The purpose of the present study was to investigate whether three different types of dietary fiber, wheat bran, carrot fiber, and citrus pectin, influenced the induction of colorectal tumors produced by 1,2-dimethylhydrazine in rats. In all groups, the tumor yield was high (87 to 97%). In the wheat bran and carrot fiber groups, the incidence of colorectal tumors was not significantly different from that of the group fed on the fiber-free basic diet. The citrus pectin group, however, had a significantly higher incidence of colorectal tumors (p less than 0.001). An increased number of auditory duct tumors was also noted in this group. In a separate experiment, dietary pectin induced a 10-fold increase in fecal beta-glucuronidase activity but did not alter this activity in the bowel wall. It has been suggested that dietary fiber protects against the induction of colorectal tumors, but this was not the case in the experiment. It is possible that the high tumor yield made the demonstration of a weak protective effect of wheat bran impossible. The reason for the increased occurrence of tumors in the citrus pectin group is obscure and will be subjected to further investigation. Fecal beta-glucuronidase activity might be one factor of importance in the activation of the carcinogen.     

Dietary ortho phenols that induce glutathione S-transferase and increase the resistance of cells to hydrogen peroxide are potential cancer chemopreventives that act by two mechanisms: the alleviation of oxidative stress and the detoxification of mutagenic xenobiotics

Oxidative stress is implicated in the etiology of cancer, hence compounds that alleviate oxidative stress by inducing enzymes that defend against free radical damage might be useful as cancer chemopreventives. Glutathione S-transferase (GST) has been suggested to be a candidate for a critical enzyme in protecting cells against free radical damage, in part, because its level of induction correlates with protection of the cell line IMR-32 against hydrogen peroxide-induced oxidative stress. The present study identified dietary ortho phenols that both induce GST and protect the cell line IMR-32 against hydrogen peroxide-caused oxidative stress. The ortho phenol (o-phenol) inducers were better protectors against oxidative stress than a number of GST inducers that did not bear phenolic groups, possibly because the phenol residues of the ortho phenols allowed their action as antioxidants as well as inducers of GST. GST has previously been thought to protect cells against cancer by detoxifying mutagenic xenobiotics. The present results suggest that ortho phenol inducers of GST might be useful as cancer chemopreventives that act by two independent mechanisms, the alleviation of oxidative stress and the detoxification of mutagenic xenobiotics.     

Inhibitory effect of microfibril wheat bran on azoxymethane-induced colon carcinogenesis in CF1 mice.

Microfibril wheat bran (MFW), a processed dietary fiber prepared by milling of coarse wheat bran (WB), is softer and has a more pleasant taste than WB. In this study, we examined the inhibitory effect of MFW on azoxymethane (AOM)-induced colon carcinogenesis in female CF1 mice and compared its effect with that of WB and cellulose (CL). The mice were fed a modified AIN 76 A diet supplemented with either MFW, WB, or CL at a final concentration of 20% (w/w). Six weekly s.c. injections of AOM (10 mg/kg body weight) were administered per mouse commencing 1 week after the start of the feeding period. Control mice were injected with saline only. Thirty-three weeks after the initial injection, the mice were sacrificed, examined for tumors, and the cecal contents were analyzed to determine the moisture content and the concentrations of short-chain fatty acids (SCFA). The average number of total tumors per mouse in the MFW (2.9 +/- 0.6, P = 0.017) and WB (5.3 +/- 1.3, P = 0.373) diet groups was lower than that of the CL diet group (7.5 +/- 1.3), though there was no significant difference in tumor incidence (94.7%, 90.0% and 94.7%, respectively) between the groups. More than 90% of the tumors in each group were adenocarcinomas. The incidence of adenoma and that of carcinoma in situ in the MFW diet group (5.3% and 0%, respectively) were also lower than those in the CL diet group (26.3 and 26.3%, respectively; P = 0.180 and P = 0.046, respectively). Analysis of the cecal contents revealed a significantly higher moisture content and significantly higher concentrations of SCFA, butyrate in particular, in the MFW and WB diet groups. The results of this study indicate that the source and texture of dietary fiber can influence tumor development in CF1 mice, and more specifically that MFW is a promising and useful dietary supplement with properties serving to protect against the development of colon cancer.     

The colonic response to genotoxic carcinogens in the rat: regulation by dietary fibre

The apoptotic response to DNA damage appears to be an innate biological mechanism for protection against tumourigenesis. It is possible that agents that protect against colorectal cancer act by enhancing the apoptotic deletion of cells suffering DNA damage, with consequent removal of those with tumourigenic mutations. We examined the acute apoptotic response to genotoxic carcinogens ("AARGC") in colonic epithelium and the possibility that dietary fibres of different fermentability might regulate AARGC. To fully define the time-course and nature of AARGC in response to the carcinogen azoxymethane (AOM), a single injection of AOM (10 mg/kg) was given to rats and apoptosis monitored in the colon by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining over a 72 h period. Having defined the site and time of maximum response, two groups of eight rats were fed diets containing 10% wheat bran fibre (WB; fermentable) or 10% methylcellulose (MC; poorly fermentable) for 4 weeks. Colonic AARGC was compared by light microscopy; lumenal short chain fatty acids (SCFAs) and pH were measured as indicators of the fermentative environment. AOM-induced AARGC was maximal at 8 h and greater in distal compared with proximal colon. Apoptotic cells were situated predominantly in the lower half of the crypt, with the median at position 9 indicating involvement of daughter as well as stem cells. There was no "second wave" of apoptosis within 72 h as follows irradiation in small intestine. Distal colonic AARGC in rats fed WB was twice that in rats fed MC (P < 0.01). Compared with MC, WB significantly lowered lumenal pH and increased all SCFAs including butyrate, while proliferation did not differ between the fibres. Certainly, dietary fibres can regulate AARGC and further studies are warranted to determine if this biological effect is the way in which dietary factors regulate tumourigenesis. Lumenal generation of butyrate may enhance AARGC as butyrate is proapoptotic in vitro.     

Biochemical epidemiology of colon cancer: effect of types of dietary fiber on fecal mutagens, acid, and neutral sterols in healthy subjects

Several epidemiological studies suggest an inverse relationship between fiber intake and colon cancer risk. Animal model studies indicate that this inhibitory effect depends on the source of dietary fiber. Because of the potential significance of certain colonic mutagens and secondary bile acids in the pathogenesis of colon cancer, the effect of types of supplemental fiber on fecal mutagens and bile acids was studied in human volunteers. Seventy-two healthy individuals consuming high-fat/moderately low-fiber diets were screened for fecal mutagenic activity using the Ames Salmonella typhimurium/microsomal assay system. Twenty-one of them were found to excrete high levels of mutagens, and 19 of them were recruited for the diet intervention study. All participants provided two 24-h stool specimens and a 4-day food record while consuming their normal (control) diet. They were then asked to consume the control diet plus 10 g of dietary fiber from wheat bran, oat fiber, or cellulose for 5 wk. After each fiber period, they were asked to consume their control diet. At the end of each fiber and control diet period, each subject provided two 24-h stool specimens. Stool samples were analyzed for bile acids and mutagens using the Ames strains TA98 and TA100 with or without S9 (microsomal) activation. The concentrations of fecal secondary bile acids (deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid) and of fecal mutagenic activity in TA98 and TA100 with and without S9 activation were significantly lower during the wheat bran and cellulose supplementation periods. Oat fiber supplementation had no such effect on these fecal constituents. Thus, the increased fiber intake in the form of wheat bran or cellulose may reduce the production and/or excretion of mutagens in the stools and decrease the concentration of fecal secondary bile acids in humans.     

Phyto-oestrogens and cancer

Phyto-oestrogens have been suggested to have a preventive effect against various cancers. This review includes a discussion of the consumption of phyto-oestrogen-rich foods such as soy, a source of isoflavones, and whole grain products, which contain lignans, and their role in the prevention of breast, prostate, and colon cancer. In women, a soy-containing diet is only slightly protective against breast cancer, if at all, but is more likely to be beneficial if initiated before puberty or during adolescence. These findings are supported by conclusions of studies of immigrants and other epidemiological studies. However, in one case-control study and one prospective study, a low-lignan diet increased the risk of breast cancer. Experimental evidence also exists for an inhibitory effect of soy and rye bran on prostate-cancer growth and for rye bran or isolated lignans on colon cancer. Whether these observed protective effects are caused by the presence of dietary phyto-oestrogens, or whether they are merely indicators of a healthy diet in general, has not been established.     

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.     

Genetic screening for colorectal cancer and intervention

There is a complex interaction between environmental/dietary factors and genetics underlying the pathogenesis of colon carcinogenesis. Little data exist concerning the impact of diet on the phenotypic expression of genetically linked colon cancer. As a result, it has been difficult to develop rationally designed dietary intervention studies in first-degree relatives of patients with established familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and other familial colon cancer syndromes. Only 2 double-blinded, placebo-controlled trials have been published concerning the use of preventive strategies in patients with genetically inherited colorectal cancer syndromes, both in patients with FAP. One study evaluated the effects of vitamin C plus vitamin E with or without a high-dose wheat bran fiber supplement on the recurrence of rectal adenomas. Over a 48-month intervention period, only the wheat bran fiber intervention significantly reduced polyp growth. A second study reported that intervention with the NSAID sulindac for 9 months in young patients with FAP resulted in a significant reduction in both polyp number and size in the rectosigmoid colon. All of the large-scale (i.e., >500 randomized participants) phase III nutrient or chemopreventive agent intervention studies thus far have targeted participants with a history of non-familial, sporadic colorectal adenomas. Current clinical adenoma trials do not measure whether the regimen being tested can prevent genotoxic events occurring in early stages of abnormal cell development that contribute to the eventual formation of adenomas nor whether the agent(s) can inhibit events occurring during the progression of adenomas to carcinomas. Therefore, future clinical trial designs may have to consider (i) lengthening the clinical trial period before adenomas develop, (ii) testing at early patient ages and/or (iii) measuring the growth of adenomas as they progress to carcinomas. © 1996 Wiley-Liss, Inc.     

Determining compliance with a dietary fiber supplement

The purpose of this pilot study was to evaluate possible ways to determine compliance with a dietary fiber supplement. A wheat bran supplement (30 g daily) significantly increased mean daily wet and dry stool weights (SW) in 7 adults, when compared to SW during an ad libitum low-fiber diet (paired t-test, P less than .01). Because unpaired data would be used during a clinical trial, distribution of the 7 ad libitum low-fiber mean SW observations was used to establish a reference distribution and an upper confidence limit against which the bran supplement SW could be compared. Only one of the seven bran supplement mean SW was above the confidence limit of the low-fiber period, independent of the number of days of collection (2-10) used to calculate the individual mean daily SW. Total fecal output over varying periods of time (2-10 days) suffered the same intersubject and intrasubject variability. Most (5-6) of the bran mean daily SW were above the group mean SW of the low-fiber period. However, this dose of bran was large enough to significantly decrease calcium absorption, and differences in SW produced by lower doses of wheat bran would probably not be as great. The bulk (greater than or equal to 80%) of a single dose of a fecal marker, chromium sesquioxide, which could be incorporated into a specific day's fiber supplement, was recovered in 5 days of excretion during the control period and in 4 days during the bran period. However, the blue color of the chromium before ingestion is clearly a negative feature. Another marker, polyethylene glycol, could not be recovered in excreta when transient time was 4 days or more. In a separate study, demonstration of very little overlap in the concentration of fecal neutral detergent fiber between the control and bran periods suggests that fecal fiber may be a marker of compliance with a fiber supplement.     

Stimulation of rat colonic crypt cell proliferative activity by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration

The effect on colonic epithelial cytokinetics of feeding a 20% wheat bran dietary supplement, either during and/or after the stage of carcinogen administration with 1,2-dimethylhydrazine, was examined in 48 male Sprague-Dawley rats fed defined diets for up to 31 weeks. Nutrient intake and body weight gain were equivalent in all groups of animals. All subgroups of rats fed bran, either during and/or after carcinogen administration, developed colonic crypt cell hyperplasia (p less than 0.05), this being greater in the proximal than in the distal colon. Autoradiographic studies showed a significant increase in proximal colonic crypt cell-labeling index, proliferation zone size, and migration distance in those rats fed wheat bran during the period of carcinogen administration (p less than 0.05). The increase in epithelial cell proliferation activity was most marked in the upper two-thirds of the crypt. These data show that there is a greater stimulation of crypt cell proliferation activity when wheat bran is consumed during the stage of carcinogen administration as compared to the stage following carcinogen exposure. This alteration in mucosal cytokinetics appears to be the mechanism by which wheat bran consumption enhances rat colon carcinogenesis during the period of dimethylhydrazine treatment.     

Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat

The environment, including diet, plays a critical role in a woman's subsequent risk of breast cancer. Two dietary polyphenols that have received attention from the health and research communities for their ability to protect against breast cancer are: genistein, a component of soy; and resveratrol, a phytoalexin found in red grapes and red wine. We and others have shown that both genistein and resveratrol can protect against mammary cancer in rodents. The timing of exposure to genistein appears critical for its mammary protective effects. It has been reported that genistein early in life causes enhanced mammary gland differentiation, alterations in cell proliferation and apoptosis, and upregulation of tumor-suppressor genes. With resveratrol in the diet, changes in cell proliferation and apoptosis in terminal ductal structures of the mammary gland might help to explain its protective effects. We conclude that genistein and resveratrol can protect against breast cancer by regulating important mammary growth and differentiation pathways.     

Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat

The environment, including diet, plays a critical role in a woman’s subsequent risk of breast cancer. Two dietary polyphenols that have received attention from the health and research communities for their ability to protect against breast cancer are: genistein, a component of soy; and resveratrol, a phytoalexin found in red grapes and red wine. We and others have shown that both genistein and resveratrol can protect against mammary cancer in rodents. The timing of exposure to genistein appears critical for its mammary protective effects. It has been reported that genistein early in life causes enhanced mammary gland differentiation, alterations in cell proliferation and apoptosis, and upregulation of tumor-suppressor genes. With resveratrol in the diet, changes in cell proliferation and apoptosis in terminal ductal structures of the mammary gland might help to explain its protective effects. We conclude that genistein and resveratrol can protect against breast cancer by regulating important mammary growth and differentiation pathways.