Folate deficiency reduces the development of colorectal cancer in rats

Carcinogenesis, Dec 2000

Alterations in folate status may play an important role in carcinogenesis. The aim of this study was to examine the effect of a diminished folate status on azoxymethane (AOM)-induced intestinal tumours in Sprague–Dawley rats. A total of 125 weanling male rats were divided into five equal groups and fed semi-purified diets containing either 8 mg/kg folate or no folate. After 4 weeks on experimental diets, all animals received three weekly subcutaneous injections of AOM at a dose rate of 15 mg/kg bodyweight. The animals were necropsied after 26 weeks. Rats with a diminished folate status, evident by significantly reduced blood and colonic folate concentrations and elevated plasma homocysteine levels, had significantly (P < 0.01) lower incidence and number of small intestinal and colonic tumours compared with rats displaying an adequate folate status. There was a significant decrease in the incidence of colonic adenocarcinomas (P < 0.01) and size of colonic tumours observed in the rats displaying a diminished folate status. This study shows that a diminished folate status was associated with a decrease in the development of AOM-induced colorectal cancers. The decrease in risk may be attributed to the known role of folate in cell multiplication.

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Folate deficiency reduces the development of colorectal cancer in rats

Richard K.Le Leu 0 2 Graeme P.Young 0 1 2 Graeme H.McIntosh 0 2 0 Abbreviations: AOM , azoxymethane; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SCFA, short chain fatty acids 1 Department of Medicine, Flinders University , Bedford Park, South Australia 5042 , Australia 2 CSIRO , Health Sciences and Nutrition, PO Box 10041 Gouger Street, Adelaide BC, South Australia 5000 2To whom correspondence should be addressed Email: Alterations in folate status may play an important role in carcinogenesis. The aim of this study was to examine the effect of a diminished folate status on azoxymethane (AOM)-induced intestinal tumours in Sprague-Dawley rats. A total of 125 weanling male rats were divided into five equal groups and fed semi-purified diets containing either 8 mg/kg folate or no folate. After 4 weeks on experimental diets, all animals received three weekly subcutaneous injections of AOM at a dose rate of 15 mg/ kg bodyweight. The animals were necropsied after 26 weeks. Rats with a diminished folate status, evident by significantly reduced blood and colonic folate concentrations and elevated plasma homocysteine levels, had significantly (P < 0.01) lower incidence and number of small intestinal and colonic tumours compared with rats displaying an adequate folate status. There was a significant decrease in the incidence of colonic adenocarcinomas (P < 0.01) and size of colonic tumours observed in the rats displaying a diminished folate status. This study shows that a diminished folate status was associated with a decrease in the development of AOM-induced colorectal cancers. The decrease in risk may be attributed to the known role of folate in cell multiplication. - Colorectal cancer is one of the most common cancers occurring in men and women in the western world (1). Dietary factors are thought to play a predominant role in the causation of colorectal cancer. Diets high in fat and/or meat and low in fruits, cereals and/or vegetables have been found to be associated with a higher risk of colorectal cancer (2,3). The reduced risk of colorectal cancer in association with consumption of fruits, cereals and vegetables may be explained by certain micronutrients (4). A higher intake of the micronutrient folate was first proposed by Freudenheim (5) to reduce the risk of colorectal cancer. Folate deficiency is one of the most prevalent vitamin deficiencies worldwide (6). Since the casecontrol study conducted by Freudenheim (5), other epidemiological studies have tended to suggest an association between diminished folate intake and increased risk of developing colorectal cancer (7). However, none of these studies relate actual folate deficiency with increased colorectal cancer risk. Animal studies performed under controlled conditions have directly examined the relationship between folate status and colorectal carcinogenesis; however, these have been somewhat inconsistent. Studies examining the effect of folate status on the development of precancerous aberrant crypt foci (ACF) lesions suggest either a promotional effect (8) or no effect with dietary folate (9), while folate deficiency was shown to lower the number of ACF (10). Folate deficiency was found to enhance the development of colonic neoplasia induced by 1,2-dimethylhydrazine when compared with rats fed diets containing 8 mg/kg folic acid (11). In another study (12), folate deficiency increased the tumour incidence and number of tumours in rats when compared with rats consuming an adequate folate diet. In a further study, folate supplementation at 2000 mg/kg was found to have increased the colon tumour size and multiplicity in rats that had been injected with the carcinogen azoxymethane (AOM) (13), while others (9) found that folate did not affect colon tumour incidence or tumour multiplicity. Other studies have also reported conflicting results (1417). These conflicting results between these experimental animal observations may well be due to variations in experimental design, diets or to differing animal models used by researchers. Folate is necessary for the biosynthesis of purines and thymine, as well as the maintenance of S-adenosylmethionine (SAM) levels for methylation reactions (18). An alteration in DNA methylation has been suggested to be an important factor in causing genetic instability (19,20) and is thought to contribute to carcinogenesis by affecting the expression of proto-oncogenes and/or tumour suppressor genes (21). DNA hypomethylation within the colon has been proposed as a possible mechanism by which folate deficiency might enhance colorectal carcinogenesis (22). The purpose of this study was to determine whether a diminished folate status might alter the development of intestinal tumours induced by AOM in male SpragueDawley rats. A secondary objective was to test if DNA methylation was altered in the folate-depleted groups. Succinylsulfathiazole (a non-absorbable antibiotic drug) was employed in some dietary treatments to (...truncated)


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Richard K. Le Leu, Graeme P. Young, Graeme H. McIntosh. Folate deficiency reduces the development of colorectal cancer in rats, Carcinogenesis, 2000, pp. 2261-2265, 21/12, DOI: 10.1093/carcin/21.12.2261