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Biomedical subjects

W R Bruce

Publications and source records attributed to W R Bruce.

At least 55 records · Page 3Linked to original sources
PubMed1989

Aberrant crypts, putative precancerous lesions, in the study of the role of diet in the aetiology of colon cancer.

Progress in the field of diet and colon cancer would be greatly enhanced by the development of a methodology which allowed for the identification and quantification of the early precursor lesions of colon cancer. Recently we described a method (Bird, 1987) consisting of staining the fixed, unsectioned colon with methylene blue for viewing the mucosal surface with the aid of a light microscope. With this methodology we observed early focal lesions in the colons of rodents which had been treated with a colon carcinogen but no lesions in the colons of control rodents. We termed these lesions aberrant crypts (AC). Based on our preliminary observations we hypothesized that AC represent precursor lesions of colon cancer. The findings from our subsequent studies (summarized in this paper) support this contention. We therefore suggest that evaluation of the characteristics of AC will further our understanding of the carcinogenic process as it occurs in the rodent colon and will provide a basis for the investigation of the role of diet in the aetiology of the disease.

Animals↗
PubMed1988

A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps.

Because supplements of vitamins C and E had been associated with reduction of fecal mutagen levels, a double-blind randomized trial was designed to examine the effects of these vitamins on the rate of recurrence of colorectal polyps, presumed precursors for colorectal cancer. Two hundred patients believed to be free of polyps after removal of at least one colorectal polyp were randomized to receive a supplement of 400 mg each of ascorbic acid and alpha-tocopherol, or a placebo. Fifteen patients had to be excluded because a review of pathology indicated that their polyps were not adenomatous. A second colonoscopic examination was planned after 2 yr of supplementation. One hundred thirty-seven people (75% of eligible subjects) completed the study; polyps were observed in the second colonoscopy in 41.4% of 70 subjects on vitamin supplements and in 50.7% of 67 subjects on placebos. After adjustment for differences between groups in demographic and dietary factors before study entry, the relative risk of polyp occurrence was 0.86, with 95% confidence limits from 0.51 to 1.45, in an analysis of 129 subjects with complete information on demographic and dietary factors who had completed the trial. Of the 48 patients who had not completed the study, 7 had died, 33 had not returned to their physician for an examination, and 8 had had a follow-up colonoscopy or sigmoidoscopy. Inclusion of the three polyps found in these eight examinations led to an estimate of relative risk of 0.86 (95% confidence limits, 0.51 to 1.43). The findings of this investigation suggest that any reduction in the rate of polyp recurrence associated with vitamin supplementation is small, and a larger study would be required to ensure that an effect of this size was not a chance finding.

Ascorbic Acid↗
PubMed1988

Proliferative activity of rectal mucosa and soluble fecal bile acids in patients with normal colons and in patients with colonic polyps or cancer.

Rectal biopsies and fecal collections were obtained from a consecutive series of 34 outpatients prior to colonoscopy at a gastroenterology clinic. Subsequently, 14 were found to have no colonic pathology, 13 had adenomatous polyps, (3 of those had a previous history of colon cancer) and 7 were diagnosed with colon cancer. In confirmation of earlier studies the tritiated thymidine labelling index was higher in patients with tumors than in those without pathology (7.9% vs. 5.8% with P = 0.06). The patients with colonic tumors also had significantly higher levels of deoxycholic acid (P = 0.01) and lithocholic acid (P = 0.005) in the aqueous extract of their feces. This study shows that these biochemical measures may indicate colon cancer risk.

Bile Acids and Salts↗
PubMed1988

Dietary factors affecting the proliferation of epithelial cells in the mouse colon.

Corn oil (CO), given as a bolus to female C57BL/6J mice, caused a marked increase in cell proliferation in the colon; this was assessed with a two-hour colchicine arrest for mitotic figures (MF) and with [3H]thymidine incorporation for labeled cells (LC) per crypt measured in histological preparations. In contrast, the same amount of fat given as a bolus in a high-fat diet mixture failed to increase cell proliferation. To determine whether a particular component in the diet was responsible for this protective effect, mice were treated with boluses of CO (0.4 ml) mixed with cellulose (CL), starch (ST), sucrose (SU), casein (CS), vitamin mix (VM) or mineral mix (MM). The results indicated that cellulose, starch, and minerals reduced the proliferative activity caused by CO (MF/crypt CO = 1.30 +/- 0.24; CO + CL = 0.55 +/- 0.10, CO + ST = 0.91 +/- 0.23, CO + MM = 0.63 +/- 0.16), whereas sucrose, casein, and vitamin mix did not. To test the implications of these findings in chronic feeding studies, groups of animals were fed (for 4 wks) diets "deficient" in starch and cellulose, calcium, and both the complex carbohydrates and calcium. The results showed that both calcium and complex carbohydrates affected the proliferation rate significantly (for instance, MF/crypt = 1.44 +/- 0.22 for both factors deficient vs. 0.48 +/- 0.05 for both factors present). We concluded that starch, cellulose, and calcium are protective for the toxic effect of CO on the mouse colon.

Animals↗
PubMed1988

Effect of high fat consumption on cell proliferation activity of colorectal mucosa and on soluble faecal bile acids.

To assess the effect of fat consumption on the proliferation of the rectal mucosa, 30 normal volunteers (22 to 71 years) were randomly allocated to three groups: (a) basal low fat diet containing 30 g of fat per day; (b) the basal diet with doses of 30 g corn oil taken with each of the three meals: 120 g fat/day; (c) the basal diet with one dose of 90 g corn oil after the last meal: 120 g fat/day. Rectal biopsies were taken 15 cm from the anal verge after five days on the diets and mucosal cell proliferation was measured by labelling index (LI). The LI was significantly (p less than 0.01) higher in group (c) (9.2) than in group (a) (5.9), with group (b) intermediate (6.8). In multiple stepwise regression analysis, the data were best fitted with age and the variable indicating fat consumed as a bolus as predictors of LI (r2 = 0.39, p less than 0.001). In separate analyses the regression coefficient with age in the fat bolus group was 0.23, p less than 0.001. There was some tendency towards lower bile acids in the faecal water in group (a) than in groups (b) and (c) following the diets and between the bile acids and LI (for lithocholic acid r = 0.48, p = 0.01). These data show that dietary fat given as a bolus can lead to an increase in the proliferation of human colonic cells, possibly as a consequence of raised levels of cytotoxic acidic lipids in the faecal stream.

Adult↗
PubMed1988

Experimental approaches to colon cancer prevention in humans.

Colorectal cancer is a major illness in the Western world. International and migrant studies suggest that environmental causes, notably a fat- and calorie-dense diet (even if adopted in adulthood), are associated with the disease. Case-control studies have not conclusively identified specific etiologic dietary factors, however. In addition, the emphasis placed on migrant studies has led many to overlook potentially important genetic factors that might help to explain some of the discrepancies in the epidemiologic data. Thus, the cause(s) of colorectal cancer remain unclear and hence effective preventive strategies are not presently available. Numerous tenable hypotheses have been generated as a consequence of observational and analytical epidemiologic studies, as well as rodent experiments. Controlled trials to test these hypotheses using colorectal cancer as an endpoint are not justifiable at present. It is possible, however, that "intermediate markers" (such as epithelial cell proliferation rates and others) that are associated with colorectal cancer in both humans and experimental animal systems might provide the means for hypothesis testing in short-term clinical trials. Despite the fact that this approach has several caveats, consistent results obtained in short-term studies would more readily justify the undertaking of a large-scale, long-term controlled study using colon cancer or adenomatous polyp recurrence as an endpoint.

Colorectal Neoplasms↗
PubMed1987

Proliferative activity of murine mammary epithelium as affected by dietary fat and calcium.

Dietary fat and calcium have been found to affect significantly the proliferative status of the mammary glands. Female mice (3-week-old C57BL/6J) were given either a low or high corn oil diet (3 or 30% by weight). One, 2, or 4 weeks after the dietary intervention the animals were given injections of [3H]thymidine and/or colchicine; 2 h later their thoracic mammary glands were removed and processed for histology and autoradiography. Animals on the high corn oil diet had an increased labeling index of both terminal ducts and mature ducts compared to the control group at each time (i.e., 10.1 +/- 2.1 versus 4.8 +/- 0.9% at 2 weeks). This effect of a high corn oil diet was evident on the mammary glands of animals at various ages. Animals on a high beef tallow diet also had a high labeling index. This effect of a high fat diet appeared to be reduced by dietary calcium. The labeling index for terminal ducts of animals on high corn oil diet decreased from 14.1 +/- 3.8, 11.9 +/- 3.4 to 8.5 +/- 1.8 and high beef tallow from 13.6 +/- 3.6, 11.4 +/- 0.7 to 9.5 +/- 1.3 for calcium levels of 0.1, 0.5, and 1.0%, respectively. Mitotic indices followed the same trend. These studies demonstrate that a high fat diet affects the proliferative status in the mouse mammary glands in a short period of time and that this effect can be reduced by dietary calcium.

Age Factors↗
PubMed1987

A CHO cell line resistant to deoxycholic acid.

Spontaneous mutants resistant to deoxycholic acid (DCA) have been selected from a CHO cell line AuxBl. One of the colonies or 'lines' selected was subsequently mutagenized by ethylmethanesulfonate (250 micrograms/ml) and a more resistant cell, named alpha 3, has been selected. When AuxBl and alpha 3 were exposed to graded concentrations of DCA for 1 h, the LD50 for the mutant strain alpha 3 was 0.66 mM compared to 0.26 mM for the parental line. AuxBl. alpha 3 showed a cross-resistance compared to AuxBl with respect to cholic acid and chenodeoxycholic acid and to other acidic lipids such as linoleic and oleic acids. As an initial step in characterization of the cell lines, the amounts of different phospholipids from whole cell extracts of the parental and mutant strains have been measured after thin-layer chromatography (TLC) separation. The results obtained demonstrated that the fraction of sphingomyelin and phosphatidylcholine over the total phospholipids was slightly increased in the resistant cell line, alpha 3, compared to the parental line, AuxBl (54.9% +/- 1.04 compared to 51.2% +/- 0.3, P = 0.01). Further characterization of cell lines resistant to bile acids could lead to the identification of the cellular target of bile acid action.

Animals↗
PubMed1987

Cellular toxicity of fecal water depends on diet.

To determine whether concentrations of potentially toxic lipids in the aqueous phase of human stool are responsive to changes in dietary fat, calcium, and fiber, 20 male volunteers were placed on a high-fat, low-calcium, low-fiber or a low-fat, high-calcium, high-fiber diet for 4 days. To assess toxicity of the fecal fractions, we examined the ability of fecal supernatants to lyse human erythrocytes. Bile acid concentrations in fecal water from the low-fat group were reduced significantly from 180 +/- 60 microM to 100 +/- 70 microM; in the high-fat group, increased from 190 +/- 60 microM to 250 +/- 100 microM. Erythrocyte lysis was 76% for the high-fat group, 37% for the low-fat group. There was a significant weak correlation between aqueous bile acid concentration and cell lysis. Results suggest that diet can influence concentrations of detergents in the aqueous phase of human stool and the potential toxicity of this fraction to cell membranes.

Adult↗
PubMed1987

Genotoxicity of two fecal steroids in murine colonic epithelium assessed by the sister chromatid exchange technique.

Two components of human feces are known to induce nuclear anomalies in mice when applied intrarectally, but to be nonmutagenic in Salmonella. We have tested these two compounds for their ability to induce sister chromatid exchanges in the colonic epithelium of mice, the same tissue in which they induce nuclear anomalies when administered by the same route. One, 4-cholesten-3-one, induced sister chromatid exchanges whereas the other, 5-alpha-cholestan-3-one did not, even at the maximum feasible dose. The results suggest that 4-cholesten-3-one is more likely to be a significant factor in human colon cancer than the 5-alpha analog.

Animals↗
PubMed1986

Characterization of cytotoxic steroids in human faeces and their putative role in the etiology of human colonic cancer.

It has been shown previously that chemically induced nuclear abeerrations in the murine colon are correlated with the carcinogenicity of the respective chemicals. Consequently, the nuclear aberration assay was utilized for the identification of putatife carcinogens in human faeces. Human fecal samples were fractionated by several chromatographic methods, and the assay led to the isolation of two substances. A combination of spectroscopic (mass, nuclear magnetic resonance, ultraviolet, and infrared) and chromatographic (HPLC and GLC) methods showed that they are 5-alpha- cholestan-3-one (I) and cholest-4-en-3-one (II). A number of C-27-C-30 steroids isolated from closely related fractions of feces were inactive in this assay. Thus I and II could play a role in etiology of large bowel cancer in humans.

Animals↗
PubMed1986

Effect of dietary fat levels on the susceptibility of colonic cells to nuclear-damaging agents.

The effect of two levels and types of dietary fats on the susceptibility of colonic cells to the nuclear-damaging effect of 1,2-dimethylhydrazine dihydrochloride (DMH), 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (MeIQ), and gamma-radiation was investigated. Corn oil and beef tallow were added to the semisynthetic diet at 5% and 20% levels (weight/weight). A diet-related effect was not evident until after two weeks of feeding. Animals (C57BL/6J female mice) that were given the 20% corn oil or beef tallow diets had significantly (p less than 0.05) more nuclear aberrations in their colons 24 hours following treatment with DMH (5 mg or 10 mg/kg body wt or MeIQ (100 mg/kg body weight) than did those given low-fat diets (5% corn oil or beef tallow). The nuclear-damaging effect of gamma radiation was unaffected by dietary treatments. A high-fat diet had the most pronounced effect on DMH-treated animals, and maximum nuclear aberrations were observed 24 hours following the treatment. Thus, we concluded that increased levels of dietary fats elevate the toxicity of DMH and MeIQ to colonic epithelial cells.

1,2-Dimethylhydrazine↗
PubMed1986

Effect of dietary calcium and cholic acid on the proliferative indices of murine colonic epithelium.

The effect of dietary calcium on the cholic acid-induced colon cell proliferative response was investigated with C57BL/6J mice. The control diets were formulated on the basis of the AIN-76 diet with the levels of calcium set at 0.1, 0.5 or 1.0% by weight and the ratio of Ca:P at approximately 1:1. Cholic acid was added at 0.1% and 0.25% by weight. The cytokinetic parameters of the colons were evaluated after 2 weeks of feeding by the metaphase arrest technique and by autoradiography. Mitotic activity was found to monotonically decrease with increasing calcium level from 0.1 to 1.0% for both the cholic acid and control groups, cholic acid-fed groups exhibiting significantly higher mitotic activity than the control groups. The effect of calcium (0.1 versus 1.0%) was evident throughout the 24-h period with both the control and cholic acid-supplemented diets. Autoradiographic analyses of the colons yielded similar results. Among the controls, the 0.1% Ca group exhibited significantly higher (P less than or equal to 0.05) crypt height, higher whole crypt labelling index and higher labelling indices at various positions along the crypt height than the 1.0% Ca group. Cholic acid-fed groups had higher values for crypt height, whole crypt labelling indices and the position of the uppermost labelled cells than the control groups. The level of calcium affected the bile acid-induced cell proliferation in the colonic epithelium; the groups fed 0.1% Ca + cholic acid had a markedly higher whole crypt labelling index, a higher position of the uppermost labelled cells and higher labelling indices at various cell positions along the crypt column compared with the 1.0% Ca + cholic acid group. The present study thus demonstrated that increased dietary calcium alleviates the mitogenic effect of a cholic acid supplemented diet on the colonic epithelium.

Animals↗
PubMed1986

Quantitation of nuclear aberrations as a screen for agents damaging to mammary epithelium.

The early nuclear damage caused by two known breast carcinogens, radiation and 7,12-dimethylbenzanthracene (DMBA), was quantitated by scoring for nuclear aberrations in mammary epithelium. Seven-week-old C57BL/6J female mice were irradiated with whole body gamma radiation or were given various doses of DMBA. The terminal end buds and ducts were separated and processed for histological preparation. The number of nuclear aberrations per 1000 cells was scored from coded slides. Animals receiving no treatment had a low level of these figures in their terminal end buds (34 +/- 7/1000 cells) but the number increased in a dose-related manner to a maximum of 161 +/- 20/1000 cells when they were treated with 8 Gy. Apoptosis in the ductal epithelium was much less frequent than in the terminal buds and the quantitation of nuclear aberrations from these structures was a less sensitive and reliable indicator of damage. DMBA and N-nitroso-N-methylurea are breast carcinogens from the polycyclic aromatic hydrocarbon and nitroso classes respectively. These chemicals cause increases in the nuclear aberration incidence in the terminal end buds but related carcinogens with different target specificities and noncarcinogens do not appear to produce such elevations. These results suggest that the quantitation of nuclear aberrations in breast epithelium might be used as a short-term, tissue-specific screen for breast carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗