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.
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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)