Chemopreventive effects of dietary folate on intestinal polyps in Apc+/-Msh2-/- mice.
Epidemiological and animal studies (reviewed in Y. I. Kim, J. Nutr. Biochemistry, 10: 66-88, 1999; J. B. Mason and T. Levesque, Oncology, 10: 1727-1743, 1996) suggest that dietary folate intake is inversely related to the risk of colorectal cancer. However, the optimal timing of folate intervention and mechanisms by which folate modulates colorectal carcinogenesis have not been clearly established. A recently developed murine model of intestinal tumorigenesis, which carries a heterozygous mutation in the Apc gene and a null mutation in the Msh2 gene (Apc+/-Msh2-/-), was used to determine the effect of dietary folate on intestinal tumorigenesis. Apc+/- Msh2-/- mice were randomized to receive either 0 or 8 mg of folate/kg diet starting at either 3 or 6 weeks of age. The 3- and 6-week diet starts represent intervention before and after the establishment of neoplastic foci, respectively. At 11 weeks of age, mice were killed, and the small intestines and colons were analyzed for adenomas and aberrant crypt foci (ACF). Serum folate concentrations were determined by a standard microbiological assay. Genomic DNA methylation was assessed by in vitro [3H]methyl incorporation into hepatic DNA and by a methyl-sensitive restriction digestion method. Microsatellite instability was determined in matched normal and polyp DNA from the small intestine and colon at 5 loci. Serum folate concentrations accurately reflected dietary folate levels (P < 0.005). Folate supplementation, started before the establishment of neoplastic foci, significantly decreased the number of small intestinal adenomas (by 2.7-fold; P = 0.004) and colonic ACF (by 2.8-fold; P = 0.028) and colonic adenomas (by 2.8-fold; P = 0.1) compared with a moderate degree of folate deficiency. In contrast, a moderately folate-deficient diet, started after the establishment of neoplastic foci, significantly reduced the number of small intestinal adenomas (by 4.2-fold; P = 0.001) but had no effect on colonic ACF and adenomas compared with folate supplementation. Genomic DNA methylation and microsatellite instability do not seem to play a major role in folate-modulated intestinal and colonic tumorigenesis in this model. In conclusion, in this murine model, dietary folate supplementation significantly protects against small intestinal and colorectal tumorigenesis if it is provided before the establishment of neoplastic foci However, if it is provided after the establishment of neoplastic foci, dietary folate seems to have an opposite effect. These data suggest that the timing of folate intervention is critical in providing an effective and safe chemopreventive effect on intestinal tumorigenesis. Notwithstanding the limitations associated with this model, our data suggest that the optimal timing of folate intervention must be established before folate supplementation can be used as a safe chemopreventive agent against colorectal cancer.
Song
J
J
Department of Nutritional Sciences, University of Toronto, Ontario, Canada.
Sohn
K J
KJ
Medline
A
A
Ash
C
C
Gallinger
S
S
Kim
Y I
YI
D000236:Adenoma / Q000517:prevention & control; D025601:Adenomatous Polyposis Coli Protein; D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000517:prevention & control*; D018899:CpG Islands / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D004032:Diet; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D007417:Intestinal Polyps / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*; D007421:Intestine, Small / Q000187:drug effects; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D011230:Precancerous Conditions / Q000188:drug therapy / Q000517:prevention & control; D011518:Proto-Oncogene Proteins / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D005492:Folic Acid; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein