W. Robert Bruce, Ph.D.,M.D.

Professor Emeritus Department of Nutritional Sciences Department of Medical Biophysics, Faculty of Medicine University of Toronto FitzGerald Building, Room 342 150 College Street Toronto ON M5S 3E2 CANADA Tel: (416) 978 5425 Fax: (416) 978 5882 E-mail:wr.bruce@utoronto.ca

Research

Colorectal cancer risk has been related to diet and lifestyle factors in many ecological, case-control and cohort studies. My goal is to understand the mechanisms responsible for these association with the expectation that such an understanding will suggest efficient approaches to colon cancer prevention.

At present, three basic mechanisms appear to be involved. First, high risk diets increase the mutation frequency in epithelial cells either because they contain genotoxic compounds such as heterocyclic amines or, perhaps more frequently, because they are deficient in vitamins that lead to the endogenous formation of genotoxic compounds such as a-oxo-aldehydes such as methylglyoxal. Second, high risk diets result in the consumption of excess calories, and the development of insulin resistance with hyperinsulinemia which acts as a growth factor. Third, high risk diets decreased epithelial membrane integrity and increase membrane permeability. This results in the exposure of epithelial cells to luminal toxins, products of inflammation and also luminal growth hormones. The combination of genotoxins and proliferation stimuli results in the accumulation of the mutations characteristic of colorectal cancer.

The importance of the three mechanisms can be evaluated in animal models and clinical studies with the use of experimental dietary interventions, markers of epithelial exposure and biomarkers of cancer risk. Typical dietary intervention might include: increased dietary thiamin, n-3 fatty acids and calcium salts; exposure biomarkers: direct chemical assessment of genotoxins and their products, plasma insulin, insulin-like growth factors, and markers of inflammation; and disease biomarkers: the putative colon cancer precursor lesions aberrant crypt foci (ACF) and colonic polyps. With reasonable hypotheses and simple methods for testing them we should be able to define the factors relating diet and colorectal cancer. The mechanisms could well be involved in other diseases associatedwith to diet lifestyle factors.

Some Recent Publications

• Bruce WR , Giacca A and Medline A. Possible mechanisms relating diet and risk of colon cancer. Cancer Epidemiol. Biomark. Prev. 9: 1271-1279, 2000.
• Naigamwalla D, Chia MC, Tran TT, Medline A, Hay K, Gallinger S and Bruce WR. Polyethylene glycol 8000 and colon carcinogenesis: inhibition in the F344 rat, promotion in the Min mouse. Cancer Res. 60: 6856-6858, 2000.
• Bruce, WR. From animal models to prevention of human colon cancer. Counterpoint: Criteria for proceeding from preclinical studies and choice of models for prevention studies. Cancer Epidemiology, Biomarkers and Prevention 12:401-404, 2003.
• Tran TT, Gupta N, Goh T, Naigamwalla D, Chia MC, Koohestani N, Mehrotra S, McKeown-Eyssen G, Giacca A and Bruce WR. Direct measure of insulin sensitivity withhyperinsulinemic-euglycemic clam and surogate measures of insulin sensitivity with ral glucose tolerance test: correlations with aberrant crypt foci promotion in rats. Cancer Epidemiology, Biomarkers and Prevention 12: 47-56, 2003.
• Bruce WR, Furrer R, Shangari N, O'Brien P, Medline A, Wang Y. Marginal Dietary Thiamin Deficienccy Induces the Formation of Colonic Aberrant Crypt Foci (ACF) in Rats. Cancer Letters 202:125-129, 2003.
• Shangari N, Bruce W R, Poon R, O'Brien PJ. Toxicity of Glyoxals - Role of Oxidative Stress. Metabolic Detoxification and Thiamine Deficiency. Biochemical Society Transactions 31: 1390-1393, 2003.