Search PubMed⌕ Search

Biomedical subjects

W R Bruce

Publications and source records attributed to W R Bruce.

At least 19 recordsLinked to original sources
PubMed2005

A pilot randomised controlled trial to reduce colorectal cancer risk markers associated with B-vitamin deficiency, insulin resistance and colonic inflammation.

Colorectal cancer risk is associated with biochemical markers for B-vitamin deficiency, insulin resistance and colonic inflammation, suggesting that these three conditions are each involved in colon carcinogenesis. We expected that dietary supplements of folic acid, n-3 fatty acids and calcium would reduce the markers and thus possibly cancer risk. We therefore randomised 98 participants, with previous colonic polyps or intramucosal carcinomas, to a combined treatment of supplementary folic acid, fish oil and calcium carbonate, or placebos for 28 days. Blood and faecal samples were obtained prior to and at the conclusion of the intervention and analysed for plasma folate, homocysteine, insulin, free fatty acids, triglycerides and faecal calprotectin. In addition, plasma vitamin B12, thiamin, glucose and C-reactive protein were assessed. Our supplemental strategy modestly affected some of the biomarkers associated with folate metabolism and insulin resistance, but had no effect on those associated with colonic inflammation. This pilot study demonstrates the feasibility and practicality of clinical trials aimed at reducing diet-related biochemical risk markers for colon cancer. We suggest that long-term intervention studies with tumour-related end points should be undertaken when the intervention agents used are found effective in short-term biochemical risk marker trials.

Adenoma↗
PubMed2003

Toxicity of glyoxals--role of oxidative stress, metabolic detoxification and thiamine deficiency.

Glyoxals are reactive alpha-oxoaldehydes that are formed endogenously from sugars, the levels of which are increased in various pathological conditions associated with hyperglycaemia and thiamine deficiency. However, the molecular cytotoxic mechanisms of glyoxal are not known. Results presented here and in the other studies cited provide a glimpse into the cytotoxicity mechanisms involved and their pathological implications. We found that glyoxal (10 microM) markedly increased the susceptibility of hepatocyte glutathione (GSH) to oxidation by hydrogen peroxide (H(2)O(2)) and markedly increased cytotoxicity by compromising the cellular antioxidant enzyme system. At higher concentrations, glyoxal was cytotoxic towards hepatocytes, which can be attributed to GSH depletion, oxidative stress and mitochondrial toxicity. Aminoguanidine or penicillamine protected the hepatocytes. Glyoxal cytotoxicity was prevented by increasing glyoxal metabolism with thiamine or NAD(P)H generators, and was increased in GSH- or thiamine-deficient hepatocytes. It was also found that feeding rats reduced thiamine levels in a diet high in simple sugars increased the number of aberrant crypt foci/colon in the absence of clinical evidence of beriberi. This was associated with decreased plasma thiamine and low erythrocyte transketolase activity. Western diets, which are frequently poor in thiamine and high in sugars, could result in increased levels of endogenous glyoxals, which in turn may lead to a predisposition to AGE (advanced glycation end-product)-related pathologies and neoplastic conditions.

Animals↗
PubMed2000

Polyethylene glycol 8000 and colon carcinogenesis: inhibition in the F344 rat, promotion in the Min mouse.

It has recently been reported that 5% polyethylene glycol 8000 (PEG 8000; Mr 8000) in the diet markedly inhibits the development of colonic tumors in carcinogen-treated rats. To assess the possible use of this agent as a preventive or treatment agent for patients with familial adenomatous polyposis, we determined the effect of PEG 8000 on spontaneous carcinogenesis in the Min mouse. PEG at a 5% concentration in the diet of Min mice did not affect the number of small intestinal or cecal tumors but did increase the number of colon tumors and the number of animals with colonic tumors (2 of 18 versus 12 of 22 animals; P < 0.001). Although the chemopreventive effect of PEG 8000 in rats is remarkable, we suggest a cautious approach in long-term testing of PEG as a chemopreventive agent for subjects at risk for colonic neoplasia.

Adenomatous Polyposis Coli↗
PubMed2000

Mechanisms linking diet and colorectal cancer: the possible role of insulin resistance.

Diet is clearly implicated in the origin of colorectal cancer, with risk factors for the disease including reduced consumption of vegetables, fiber, and starch and increased consumption of red meat and animal fat. Several hypotheses have been developed to explain these associations. Most recently, McKeown-Eyssen and Giovannucci noted the similarity of the risk factors for colorectal cancer and those for insulin resistance and suggested that insulin resistance leads to colorectal cancer through the growth-promoting effect of elevated levels of insulin, glucose, or triglycerides. We briefly review the evidence from observational, epidemiological, and experimental animal studies linking diet with insulin resistance and colorectal cancer. The evidence suggests that diets high in energy and saturated fat and with high glycemic index carbohydrate and low levels of fiber and n-3 fatty acids lead to insulin resistance with hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. We then consider how insulin, the related insulin-like growth factors, triglycerides, and nonesterified fatty acids could lead to increased growth of colon cancer precursor lesions and the development of colorectal cancer. Finally, we consider the implications of this scheme on possible future research directions, including studies of satiety and clinical tests of the importance of insulin resistance in the colon carcinogenesis process.

Animals↗
PubMed2000

Possible mechanisms relating diet and risk of colon cancer.

Two recent developments in cancer epidemiology and experimental carcinogenesis provide the basis for two possible mechanisms relating diet and colon cancer risk. The first development is the accumulating epidemiological evidence for an association between insulin resistance and colonic adenomas and cancers. This evidence suggests the following mechanism: the consumption of excess dietary energy results in the development of insulin resistance with increased circulating levels of insulin, triglycerides, and non-esterified fatty acids. These circulating factors subject colonic epithelial cells to a proliferative stimulus and also expose them to reactive oxygen intermediates. These long-term exposures result in the promotion of colon cancer. The second development is the continuing identification of agents that significantly inhibit experimental colon carcinogenesis. These observations suggest the following mechanism: focal loss of epithelial barrier function resulting from a failure of terminal differentiation results in the "leak" of a presently undefined toxin and a focal inflammatory response characterized by evidence of the activation of the COX-2 enzyme and an oxidative stress with the release of reactive oxygen intermediates. The resulting focal proliferation and mutagenesis give rise to aberrant crypt foci and adenomas. The process is inhibited by: (a) demulcents confined to the colonic lumen that "repair" the surface; (b) anti-inflammatory agents; or (c) antioxidants. The two mechanisms, i.e., insulin resistance acting throughout the body and focal epithelial barrier failure acting locally, can describe most of the known relationships between diet and colon cancer risk.

Carcinogens↗
PubMed1998

Rapid quantitation of thermal oxidation products in fats and oils by 1H-NMR spectroscopy.

This work describes the application of high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy to the study of the thermal peroxidation of beef tallow and corn oil under standardized conditions. The approach provides a rapid, quantitative method for determining the degree of oxidation of unsaturated fatty acids in animal and vegetable fats and oils by quantitating the decreasing intensities of 1H-NMR peaks for allylic and olefinic protons in unsaturated fatty acid chains of triglycerides and the increasing peak intensities of hydroperoxide and saturated and alpha, beta-unsaturated aldehydic protons in relation to the less labile protons in the triglyceride molecule. Two-dimensional correlation spectroscopy analysis of highly oxidized beef tallow (180 degrees C for 24 h) suggested that the unsaturated aldehydes that persisted were apparently associated with carboxy groups.

Animals↗
PubMed1998

Thermally oxidized dietary fat and colon carcinogenesis in rodents.

Thermally oxidized animal fat (beef tallow) was assessed for colon cancer-promoting and -initiating activity in F-344 rats and CF-1 mice with the use of the aberrant crypt focus (ACF) assay. In two promotion studies, extensively oxidized beef tallow (110 degrees C for 144-168 h, peroxide value approx 200 meq/kg, with > 80% loss of allylic and olefinic protons) had relatively little effect on the growth of ACF in F-344 rats. The multiplication constant for treatment/control of ACF size in aberrant crypts per ACF at 100 days was 1.07 (95% confidence interval = 1.01-1.14) and 0.98 (95% confidence interval = 0.91-1.06). ACF size was not affected by less extensively oxidized beef tallow or by a 10-fold reduction of dietary alpha-tocopherol during the growth of the ACF. In initiation studies, extensively oxidized beef tallow administered by gavage increased the number of animals with ACF and the number of ACF per colon (11 of 23 and 5 of 29 animals with ACF; 1.09 +/- 0.29 and 0.21 +/- 0.09 ACF/colon, respectively). Less severely oxidized beef tallow was without effect. Further studies with CF-1 mice confirmed that extensively oxidized beef tallow increased numbers of animals with ACF and average ACF per colon. The unsaturated aldehyde acrolein was without effect in the ACF assay. These data suggest that highly thermolyzed beef tallow contains an uncharacterized initiator or leads to conditions in which spontaneously initiated ACF are increased.

Acrolein↗
PubMed1998

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy.

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.

Animals↗
PubMed1997

Insulin resistance and promotion of aberrant crypt foci in the colons of rats on a high-fat diet.

McKeown-Eyssen and Giovannucci recently proposed that the etiology of insulin resistance (IR) and colorectal cancer (CRC) are related. They suggested that diets high in fat and energy and low in complex carbohydrates and a sedentary life-style lead to IR and that the associated hyperinsulinemia, hypertriglyceridemia, and glycemia lead to increased CRC risk through the growth-promoting effect of insulin or the increased availability of energy. We reasoned that if diet affects colon carcinogenesis through its effect on IR, evidence of colon cancer promotion would be preceded by evidence of IR. To test this expectation, we compared the effects of a high-fat (HF, 59% energy) diet and a low-fat (LF, 11% energy) diet on indirect measures of IR and promotion in azoxymethane-initiated F344 rats. Promotion was assessed as growth of aberrant crypt foci (ACF) at 100 days after initiation. The HF diet increased ACF size 1.4 times (95% confidence interval = 1.30-1.58) that of the LF diet. The HF diet also led to impaired oral glucose tolerance tests measured at 4, 32, 60, and 88 days and characterized by an average increased glucose concentration of 0.78 +/- 0.17 mmol/l (p < 0.001). It also resulted in an impaired intravenous glucose tolerance test and elevated levels of serum insulin after a glucose gavage. We concluded that with this model a high-fat diet leads to evidence of IR before it is possible to demonstrate CRC promotion, thus providing support, necessary but not sufficient, for the causal hypothesis linking IR and CRC. Possible mechanisms linking diet, IR, and promotion are considered.

Administration, Oral↗
PubMed1996

Natural history of aberrant crypt foci. A surgical approach.

BACKGROUND: The aberrant crypt focus (ACF) appears to be an important early step in colorectal carcinogenesis. Our objectives were to determine the natural history of ACF in a surgical model. METHODS: The natural history of ACF was followed by marking the lesions in vivo with tattoos. Rats were given four weekly injections of azoxymethand (AOM; 20 mg/kg). One hundred days after the first injection of AOM, rats were anesthetized, and individual aberrant crypt focus was identified by staining with methylene blue. A 3 x 3 mm area, identifying one large (4-8 crypts) ACF was marked with a tattoo dye in each colon. Control animals received saline or AOM injections and were tattooed in areas without ACF. At 200 days, colons were examined for the presence of macroscopic lesions. RESULTS: A total of 54 tumors were found in the study group of 38 animals, and 21 of these were in the transverse and proximal descending colon. The marked areas (all in transverse and proximal descending colon) yielded 6 tumors and 2 ACF, but in 30 instances no abnormality was noted. Probability of observing a tumor in the 3 x 3 mm area of the colon that was identified as containing ACFs was 17 times greater than expected from the observed tumor rate in approximately the same zone (16 vs. 1.7 percent; 95 confidence interval, 10 to 22 and 0.5 to 1.3 percent). Twenty control animals receiving saline had no tumors of epithelial origin. Nine control animals that were carcinogen-treated and tattooed in areas without ACF had no tumors in the marked areas. CONCLUSION: Results thus show regression of many ACF identified early in the carcinogenesis process. Results also support the hypothesis that some ACF are precursor lesions for adenomas and cancers.

Adenoma↗
PubMed1996

Dietary cholesterol inhibits the development of aberrant crypt foci in the colon.

We evaluated the effect of dietary cholesterol and oxidized cholesterol on the promotion of aberrant crypt foci (ACF), which are putative precancerous lesions in the colon. Sixty female C57BL/6J mice were given four weekly injections (ip) of azoxymethane (AOM) then fed either a control AIN-76 diet or the control diet supplemented with 0.3% cholesterol or 0.3% oxidized cholesterol for 100 days. The oxidized cholesterol was prepared by heating cholesterol at 110 degrees C for 48 hours. Gas chromatographic analysis of the oxidized cholesterol showed that 96% of the cholesterol was unchanged and less than 2% of the cholesterol was oxidized. The remaining 2% impurities were unidentified and present in both the cholesterol and heated cholesterol. The number of ACF in the group fed cholesterol was significantly lower than the control group (7.9 +/- 1.0 vs. 12.5 +/- 1.2, p < 0.01). The number of ACF in the group fed oxidized cholesterol (10.1 +/- 1.1) was not different from the control or cholesterol groups. The size of the ACF (no. of crypts per focus) did not differ between the three dietary groups. Serum low-density lipoprotein (LDL) cholesterol was greater in the cholesterol-fed group than the control group (40.5 +/- 4.6 vs. 24.3 +/- 3.6 mg/dl, p < 0.05). LDL cholesterol from the animals fed oxidized cholesterol (37.7 +/- 4.7 mg/dl) was not different from the control or cholesterol-fed animals. Total and high-density lipoprotein (HDL) cholesterol did not differ between the groups. The results show that dietary cholesterol significantly inhibits the promotion of ACF in the colon. The elevated LDL cholesterol may inhibit de novo cholesterol synthesis in the preneoplastic colonic epithelial cells, thereby inhibiting DNA synthesis and cell proliferation.

Animals↗
PubMed1996

Inhibition of rat mammary tumorigenesis by dietary cholesterol.

The effects of dietary cholesterol and oxidized cholesterol on mammary tumor development were examined in female Sprague-Dawley rats exposed to the carcinogen N-methyl-N-nitrosourea (MNU). Animals were administered 50 mg/kg MNU at 50 days of age and fed either a control (AIN-76) diet or the control diet supplemented with 0.3% cholesterol or 0.3% oxidized cholesterol for up to 26 weeks. The oxidized cholesterol was prepared by heating cholesterol at 110 degrees C for 48 h. Gas chromatographic analysis of the oxidized cholesterol revealed a 2% yield of oxidation products in addition to a large amount of unchanged cholesterol (> 96%). Tumor incidence in the cholesterol group (67%) was significantly lower than in the control group (96%, P < 0.05), but the oxidized cholesterol group (79%) was not significantly different from the control or cholesterol groups. Average number of tumors per animal was lower in the cholesterol group (1.5) than in the control (2.8) or oxidized cholesterol groups (2.3, P < 0.005). Serum low density lipoprotein (LDL) cholesterol was greater in the cholesterol (185 +/- 38 mg/dl) and the oxidized cholesterol groups (160 +/- 34 mg/dl) than in the controls (55 +/- 4 mg/dl, P < 0.05), although there was no difference between the cholesterol and the oxidized cholesterol groups. These results show that dietary cholesterol inhibits mammary tumor development in this model. Elevated serum LDL cholesterol may inhibit de novo cholesterol synthesis in preneoplastic and/or tumor cells, thereby inhibiting their proliferation.

Animals↗
PubMed1996

Insulin promotion of colon tumors in rats.

McKeown-Eyssen and Giovannucci have proposed a mechanism for colon carcinogenesis based on the similarity of the risk factors for colorectal cancer and non-insulin-dependent diabetes. They note that diets high in fat and energy and low in complex carbohydrates and a sedentary lifestyle lead to insulin resistance and hyperinsulinemia and propose that the hyperinsulinemia promotes colon carcinogenesis. In this study, we directly tested for a promoting effect of insulin on colon carcinogenesis in F344 rats. After azoxymethane initiation and injections of insulin given 5 times/week for 17 weeks, the fraction of rats with colon tumors was greater in rats receiving insulin than in rats receiving saline (79 versus 50%, respectively; P < 0.05 for tumors with maximum diameters > or = 2 mm), and the average number of tumors/ rat was also greater (2.00 versus 0.73; P < 0.001). There was no effect on body weight. Our results demonstrate that insulin in a colon tumor promoter in this rat model and support the proposed mechanism linking lifestyle factors and colon carcinogenesis.

Animals↗
PubMed1995

Colonic protein fermentation and promotion of colon carcinogenesis by thermolyzed casein.

Thermolyzed casein is known to promote the growth of aberrant crypt foci (ACF) and colon cancer when it is fed to rats that have been initiated with azoxymethane. We speculated that the promotion was a consequence of increased colonic protein fermentation (i.e., that the thermolysis of the casein decreases its digestibility, increases the amount of protein reaching the colon, and increases colonic protein fermentation and that the potentially toxic products of this fermentation promote colon carcinogenesis). We found that the thermolysis of casein reduces its digestibility and increases colonic protein fermentation, as assessed by fecal ammonium and urinary phenol, cresol, and indol-3-ol. Thermolysis of two other proteins, soy and egg white protein, also increases colonic protein fermentation with increased fecal ammonia and urinary phenols, and thermolysis of all three proteins increases the levels of ammonia and butyric, valeric, and i-valeric acids in the cecal contents. We found, however, that the increased protein fermentation observed with thermolysis is not associated with promotion of colon carcinogenesis. With casein, the kinetics of protein fermentation with increasing thermolysis time are clearly different from the kinetics of promotion of ACF growth. The formation of the fermentation products was highest when the protein was thermolyzed for one hour, whereas promotion was highest for protein that had been thermolyzed for two or more hours. With soy and egg white, thermolysis increased colonic protein fermentation but did not promote colon carcinogenesis. Thus, although thermolysis of dietary casein increases colonic protein fermentation, products of this fermentation do not appear to be responsible for the promotion of colon carcinogenesis. Indeed, the results suggest that protein fermentation products do not play an important role in colon cancer promotion.

Animals↗
PubMed1994

A randomized trial of a low fat high fibre diet in the recurrence of colorectal polyps. Toronto Polyp Prevention Group.

After polypectomy for adenomatous colorectal polyps, 201 persons were randomized to receive counselling on a diet low in fat (the lesser of 50 g/day or 20% of energy) and high in fibre (50 g/day) (LFHF), or to follow a normal western diet (ND), high in fat and low in fibre. After 12 months of counselling, fat consumption was about 25% of energy in the LFHF group and 33% in the ND group; fibre consumption was 35 g and 16 g respectively. After an average of two years of follow-up, an intention to treat analysis led to a ratio of cumulative incidence rates of 1.2 (95% CL 0.6-2.2) for recurrence of neoplastic polyps, a finding which suggests no significant difference between dietary groups over the period of observation. An exploratory analysis conducted among 142 persons with substantial diet counselling indicated a reduced risk of neoplastic polyp recurrence in women (RR = 0.5), associated with reduced concentrations of faecal bile acids while on the LFHF diet, but indicated an increased risk of recurrence in men (RR = 2.1), associated with increased faecal bile acids. Although a larger study would be needed to rule out the role of chance, these findings of gender-specific associations between diet counselling and both faecal bile acid concentrations and recurrence of colorectal neoplasia are consistent with recently published evidence of differences between genders.

Adenomatous Polyps↗