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W R Bruce

Publications and source records attributed to W R Bruce.

At least 37 records · Page 2Linked to original sources
PubMed1993

Diet, aberrant crypt foci and colorectal cancer.

We have used the aberrant crypt focus (ACF) assay to test and develop hypotheses linking diet and colon cancer. The hypotheses were suggested by epidemiological studies that identified possible dietary factors associated with colorectal cancer risk. The ACF assay was used to quantitate the effect of the dietary factors on the initiation and growth of these putative precursors of colon cancers in experimental animals. Using this approach we have developed 3 new hypotheses for the role of diet in colorectal cancer. These are (1) a risk associated with 5-hydroxymethyl-2-furaldehyde in caramelized sugar, (2) a risk associated with some factor in thermolyzed casein, and (3) a risk associated with single nutrient boluses of sucrose and fructose. The importance of these hypotheses has still to be tested in long term carcinogenesis experiments, in analytic epidemiology studies and then, perhaps, in intervention trials.

Animals↗
PubMed1993

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

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

Animals↗
PubMed1993

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

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

Animals↗
PubMed1993

K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis.

Ras mutations are an important early event in a number of carcinogen-induced rodent tumors. Colon carcinogenesis induced in rats by azoxymethane is a useful model as it mimics the adenoma-carcinoma sequence observed in humans. In addition, aberrant crypt foci develop in the rat and these lesions appear to be potentially important precursors to adenomas in colorectal cancer. Recent studies have shown that specific K-ras codon 12 and 13 mutations are present in up to 66% of carcinogen-induced rat colon adenocarcinomas. We studied the frequency of these mutations during the aberrant crypt focus-adenoma-carcinoma sequence in azoxymethane-induced Fisher F344 rats. K-ras codon 12 GAT and codon 13 GAC mutations were detected with a sensitive assay based on the amplification of DNA using the polymerase chain reaction. No mutations were present in normal mucosa. Of 27 aberrant crypt foci, K-ras mutations were identified in 2 lesions containing 5 and 10 aberrant crypts, respectively. Mutations were present in 1 of 23 and 10 of 27 adenomas and adenocarcinomas, respectively. These data suggest that K-ras mutations play a role during the stages of carcinogenesis in azoxymethane-induced rat colon cancer. The demonstration of a genetic mutation in aberrant crypt foci provides further evidence for the significance of these lesions as precursor markers of malignant potential during colorectal tumorigenesis.

Adenocarcinoma↗
PubMed1992

Promotion of aberrant crypt foci and cancer in rat colon by thermolyzed protein.

BACKGROUND: We have previously shown that thermolyzed protein (casein) cooked with fat in the diet of the rat promotes the growth of aberrant crypt foci (putative precursors of colon cancer) assessed at 100 days. PURPOSE: To determine how thermolysis affects this promotion, we examined thermolysis conditions, quantity of thermolyzed protein in the diet, and duration of thermolysis. To determine whether the previous finding of promotion of aberrant crypt foci corresponds to promotion of cancers assessed much later, we carried out promotion studies until colon cancers appeared. METHODS: F344 rats were given an initiating dose of azoxymethane and were then randomly allocated to groups receiving diets differing in their quantity and quality of casein. The groups were examined for aberrant crypt foci and tumors in the colon. RESULTS: Aberrant crypt foci were promoted by diets containing thermolyzed casein (180 degrees C, 2 hours). Promotion increased with increasing level of thermolyzed casein in the diet (to 20%) and with increasing thermolysis time (to 4 hours). The number of animals with polyps and cancers was higher in the animals receiving thermolyzed protein (2 hours), 16/23 versus 9/26 (P less than .05) and 10/26 versus 3/27 (P less than .05), respectively. The number of aberrant crypts per focus and the number of large aberrant crypt foci were higher in the tumor-bearing animals. CONCLUSIONS: Thermolyzed casein promotes early colonic precursor lesions in a dose-dependent and thermolysis time-dependent manner; thermolyzed casein also promotes colon cancer. IMPLICATIONS: The promoter formed on thermolysis could be involved in colon cancers associated with diets cooked at elevated temperatures, such as can occur with high-fat diets.

Animals↗
PubMed1992

The effect of lowering faecal pH on the rate of proliferation of the normal colonic mucosa.

Epidemiological and animal studies suggest that faecal pH may be a risk factor for colorectal cancer with low faecal pH associated with a lower incidence of the disease. The aim of this study was to determine whether faecal pH (or dietary fibre) affects the short-term risk factors for colon cancer. Sixty-nine normal volunteers were randomized into three equal groups (A-C). They provided food records, faecal specimens and submitted to rectal biopsy for thymidine labelling studies before and after a 2-week intervention. Group A received a placebo of fruit juice. Group B, approximately 3.0 g d-1 sodium sulphate in juice. Group C, 30 g d-1 supplementary dietary fibre as wheat bran in bread. Age, sex, weight, height and intake of macronutrients and minerals were similar in the groups prior to intervention. Faecal pH was similar for the three groups before and was reduced in Group B after intervention (P = 0.001) with a relative reduction of 0.5 pH units. The labelling index for the three groups was similar prior to intervention; after, it was lowest in Group B with a relative reduction of 0.5% points, although this difference was not statistically significant. The results thus do not support the hypothesis that an acidification of faecal pH leads to a reduction in risk markers for colon cancer.

Adult↗
PubMed1992

Colonic fermentation and markers of colorectal-cancer risk.

The aim of this study was to determine the effect of soluble fiber on indexes of colon-cancer risk in postpolypectomy and nonpolyp patients. Forty-five postpolypectomy and 49 nonpolyp volunteers completed 2-wk metabolic studies where half of the group received oat-bran supplements and the other half took wheat-brain supplements. Colonic biopsies taken before and after the intervention showed no difference in the index of thymidine colonic-crypt-cell labeling, thymidine-labeling pattern, or nuclear aberrations. Nevertheless, fecal pH was significantly reduced by 0.23 +/- 0.07 pH units (P less than 0.002) as an index of increased colonic fermentation on oat bran. This was not associated with increased basal breath hydrogen concentrations; fecal butyrate concentrations were higher on wheat bran. We conclude that soluble fiber as oat brain appears to have no advantage over wheat bran in modifying putative risk factors for colonic cancer.

Butyrates↗
PubMed1992

Wheat-bran and oat-bran supplements' effects on blood lipids and lipoproteins.

To compare the effects of oat-bran fiber on blood lipids, we studied 84 healthy middle-aged men and women who were placed on metabolic diets, for 2 wk, that were supplemented with either wheat bran (n = 42) or oat bran (n = 42). Fiber supplementation was 1.6 micrograms dietary fiber/J (6.8 g dietary fiber/1000 kcal) to a maximum of 16.4 g fiber/d. Significantly greater decrease with oat than with wheat were seen in total cholesterol (0.56 +/- 0.08 mmol/L and 0.29 +/- 0.08 mmol/L, P = 0.022) and low-density-lipoprotein cholesterol (0.39 +/- 0.07 mmol/L and 0.15 +/- 0.07 mmol/L, P = 0.024). No significant differences were seen in high-density lipoprotein, apolipoproteins A-1 and B, or triglyceride. We conclude that oat bran has an advantage over wheat bran in lowering serum lipids when tested in metabolic diets on large numbers of individuals with an initial mean serum cholesterol concentration above the desirable range, at 5.61 +/- 0.16 mmol/L.

Adult↗
PubMed1992

Aberrant crypt foci and microadenoma as markers for colon cancer.

Foci of aberrant crypts similar to those seen in experimental animals exposed to colon carcinogens have been identified and quantified on the mucosal surface of fixed resections of human colon after methylene blue staining. Many of the foci in humans showed dysplasia on histologic examination and were considered to be microadenoma (MA). These lesions may be precursors for adenomatous polyps and colorectal cancer. Rats and mice initiated with azoxymethane, then fed diets containing sucrose or casein heated at 180 degrees C to stimulate normal cooking conditions, had three to five times more large MA after 100 days than controls. Thus, cooked sugar and protein contain promoters of the growth of colonic MA. 5-Hydroxymethylfuraldehyde was identified as a promoter in cooked sugar.

Adenoma↗
PubMed1991

Identification and quantification of aberrant crypt foci and microadenomas in the human colon.

The objective of the present study was to determine whether aberrant crypt foci (ACF) similar to those observed in the colons of experimental animals exposed to colon carcinogens could be identified and quantified in the human colon. Twenty-seven colon resections from patients affected by familial adenomatous polyposis (FAP, five cases), colorectal cancer (CRC, 12 cases), and benign diseases of the large bowel (BD, 10 cases) were collected from a pathology repository or immediately after operation. Ten or more 1-cm2 formalin-fixed, methylene-blue--stained samples of colonic mucosa from each colon were scored under light microscopy for ACF. The number of ACF per cm2 and the number of crypts per ACF for each colon were calculated. The average number of ACF per cm2 in the FAP group (20 +/- 19, mean +/- SD) was significantly higher (P less than 0.01) than those of the CRC (0.37 +/- 0.41) and BD (0.18 +/- 0.35) groups. At least one ACF was found in every colon resection from CRC patients and in six out of 10 colon resections from the BD group. The average number of crypts per ACF ranged from five to 35 with absolute values from 1 to over 100. Fifty-five histologic specimens, 43 with ACF of various size and 12 without, were prepared by sectioning the colon parallel to the mucosal surface. There was a close correlation between the number of crypts per ACF in each specimen as scored by methylene-blue and histologic examination. Twenty-six aberrant crypt foci displayed dysplasia as evident by histologic analysis. In these instances we feel the term microadenoma is appropriate and, using this unique approach of examining the human colon, they can be easily identified and quantified. These lesions may well be precursors for adenomatous polyps and colorectal cancer.

Adenoma↗
PubMed1991

Effect of high-fat and low-fiber meals on the cell proliferation activity of colorectal mucosa.

Normal healthy volunteers (n = 43) were divided into four groups that received diets providing low or high levels of dietary fat (33 or 96 g/day) and low or high levels of dietary fiber (6 and 41 g/day) for a period of five days. Proliferation was assessed with tritiated thymidine labeling of three rectal biopsies. After five days on the prescribed diets, the average thymidine labeling index (LI) of the group on the high fat-low fiber diet was only 25% higher than the average LI of the group on the low fat-high fiber diet, a difference that is not statistically significant. We conclude that a short-term increase in dietary fat and decrease in dietary fiber does not result in a large increase in cell proliferation rate.

Adult↗
PubMed1990

Promotion of colonic microadenoma growth in mice and rats fed cooked sugar or cooked casein and fat.

We studied the effect of cooked food components on the promotion of microadenoma growth in the colons of mice and rats. CF1 mice and Fisher 344 rats were initiated with azoxymethane, with 152 mice receiving four weekly i.p. injections of 5 mg/kg, 59 rats receiving a single injection of 20 mg/kg, and 24 rats receiving 30 mg/kg. A week after the last injection, the animals were randomly assigned to one of eight diets with identical ingredients, but the three components, sucrose, casein, and beef tallow, either uncooked or cooked. Control animals were given diets with uncooked ingredients. Experimental animals were fed diets in which one, two, or three of the components were cooked in an oven at 180 degrees C until golden brown before they were added to the diet. After 100 days on the diets, the colons were fixed, stained with methylene blue, and scored for microadenomas. The mice and the rats fed cooked sucrose, or casein and beef tallow cooked together, had three to five times more large microadenomas than did the controls (P ranging from 0.02 to 0.0001). No significant increase was observed with the five other cooked diets. Two rats fed the casein and beef tallow cooked together had adenocarcinomas. Thus, a diet containing 20% of cooked sucrose, or 40% of casein and beef tallow cooked together, promotes the growth of colonic microadenomas in initiated mice and rats, and would appear to contain promoters for colon cancer.

Adenoma↗
PubMed1990

Effects of sodium sulfate on fecal pH and proliferation of colonic mucosa in patients at high risk for colon cancer.

High fecal pH level has been suggested as a risk factor for colorectal cancer. We previously demonstrated that, although sodium sulfate did not affect the proliferation rate of colonic mucosa, as indicated by thymidine-labeling index, it did lower fecal pH in subjects at average risk for colon cancer. In the current study, we evaluated the effects of sodium sulfate on fecal pH and proliferation of colonic mucosa in subjects at high risk for colon cancer. Fifty-seven patients who had had colonic polyps removed were randomly assigned to two groups to receive either sodium sulfate (27 patients) or a placebo (25 patients) at a mean dose of 4 g/day for 14 days. Age, sex, height, and weight were comparable in both groups. Before intervention, levels of fecal pH were similar in the two groups, but after intervention, fecal pH was reduced only in the sodium sulfate group (mean decrease, 0.3 U; P less than .01). Thymidine-labeling index (number of labeled cells per number of cells counted) was similar in the two groups prior to intervention and did not change significantly after intervention (mean increase, 0.9%; P = .35). Regression analysis revealed no correlation between the change in labeling index and the change in fecal pH. We conclude that high fecal pH level is only indirectly associated with the development of colon cancer and, therefore, may be a secondary, rather than a primary, measure of cancer risk.

Adult↗
PubMed1990

Short-term tests and long-term prospects for colon cancer prevention.

Five assay systems that have been used for identifying possible carcinogenic factors responsible for human colon cancer are described. These are: Salmonella, colonic micronuclei, colonic epithelial proliferation and aberrant crypt assays, and polyp recurrence trials. The assays have led to the development and testing of 7 hypotheses. A review of this process points to the importance of specificity in the assay system.

Animals↗
PubMed1990

Manipulation of fecal pH by dietary means.

Epidemiological and animal studies suggest that colonic fermentation and fecal pH may be risk factors for colorectal cancer. To modify these factors, we sought to develop a simple instrument for use in intervention studies. Three 14-day studies with 32, 40, and 30 healthy volunteers maintained on their regular diet were carried out to evaluate the effect of various food supplements on fecal pH. The interventions tested included supplementary lactulose, Metamucil, oat bran, wheat bran, or no supplement. The results showed that it is possible to provide a simple intervention to reduce fecal pH by 0.4 unit with oat bran administered at 75-100 g/day over a 14-day period, using a wheat combination, equivalent in macronutrients and fiber, as a control.

Adult↗
PubMed1989

Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods.

Aberrant crypt foci can be identified in the colons of rodents treated 3 wk earlier with azoxymethane, a known colon carcinogen. These crypts can easily be visualized in the unsectioned methylene blue-stained colons under light microscopy, where they are distinguished by their increased size, more prominent epithelial cells, and pericryptal space. They occur as single aberrant crypts or as two, three, or four aberrant crypts in a cluster. We compared the reported ability of carcinogens associated with the human diet to induce colon cancer with the measured rate of induction of aberrant crypts in female CF1 mice and Sprague-Dawley rats. The carcinogens used were 1,2-dimethylhydrazine, methyl nitrosourea, N-nitrosodimethylamine, benzo(a)pyrene, aflatoxin B1, 2-amino-6-methyldipyrido[1,2-alpha:3',2'-d]imidazole, 2-amino-3-methylimidazo[4,5-P]quinoline, 2-amino-3,4-dimethylimidazo[4,5-P]quinoline, and 3-amino-1-methyl-5H-pyrido[4,3-b]indole. Graded doses of these compounds were given to the animals by gavage twice with a 4-day interval, and the animals were terminated 3 wk later. All colon carcinogens induced aberrant crypts in a dose-related fashion. N-Nitrosodimethylamine and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, carcinogenic compounds that do not induce colon cancer, did not induce them. The ability of the studied compounds to induce aberrant crypts was species specific; e.g., aflatoxin B1 and 2-amino-3,4-dimethylimidazo[4,5-P]quinoline induce about 20 times more in rats than mice. This relationship was consistent with their reported ability to induce colon cancer in these species. Results of the present study support the use of the aberrant crypt assays to screen colon-specific carcinogens and to study the process of colon carcinogenesis.

Animals↗
PubMed1989

Effect of calcium supplementation on mucosal cell proliferation in high risk patients for colon cancer.

Recent findings suggest that supplemental calcium could lower the abnormally high proliferation rate found in the colonic mucosa of subjects at high risk for colon cancer. In this double blind controlled study, this effect in volunteers previously operated upon for a colorectal adenocarcinoma was tested. Thirty subjects were randomised to receive either elemental calcium 1200 mg/day or a placebo. Mucosal proliferation was measured with tritiated thymidine labelling before and after the 30 day intervention period. Diets, faecal pH and the concentration of calcium and bile acids in the aqueous phase of feaces were also measured. Labelling index did not differ significantly in the two groups before intervention (placebo 4.0(2.4) v calcium 4.9(2.9), but the difference approached significance afterwards (4.4(2.4) v 6.5(3.4), p = 0.06). Individual changes occurring with intervention were tabulated and comparison of the means for the groups was not significant (delta = 0.3 vs delta = 1.8, p = 0.11). Calcium concentration, faecal pH and deoxycholic acid concentration increased in the calcium group (p = 0.02, 0.005 and 0.004 respectively). Calcium does not show any effect in decreasing colonic mucosal proliferation in this high risk group for colon cancer; it may increase faecal pH and the production of deoxycholic acid in the colon.

Aged↗