Effects of dietary folate on ulcerative colitis-associated colorectal carcinogenesis in the interleukin 2- and beta(2)-microglobulin-deficient mice.
Folate supplementation may reduce the risk of colorectal dysplasia and cancer in subjects with chronic ulcerative colitis (UC). The interleukin (IL) 2- and beta(2)-microglobulin (beta(2)m)-deficient (IL-2(null) x beta(2)m(null)) mice spontaneously develop colon cancer in the setting of chronic UC. This study investigated the effects of dietary folate on the development of UC-associated colon cancer in the IL-2(null) x beta(2)m(null) mice. Weaning IL-2(null) x beta(2)m(null) mice were randomized to receive 0 (deficient; n = 40), 2 (basal requirement; control; n = 46), or 8 (supplemented; n = 36) mg folate/kg diet for 32 weeks. At necropsy, all macroscopic colonic tumors were identified and histologically classified as dysplasia or adenocarcinoma. The incidence of high-grade lesions (high-grade dysplasia/carcinoma in situ and invasive adenocarcinoma) in the folate-supplemented group was 46% lower than that in the control group (35.3% versus 65.1%, P = 0.009). The incidence of high-grade lesions in the folate-deficient group was also 49% lower than that in the control group (33.3% versus 65.1%, P = 0.007). The higher mortality rate in the folate-deficient group compared with the other two groups (25% versus 6.5% and 5.6%, P < 0.02) partially accounted for the low incidence of high-grade lesions in this group. These data indicate that dietary folate supplementation at 4x the basal dietary requirement significantly suppresses UC-associated colorectal carcinogenesis in the IL-2(null) x beta(2)m(null) mice. These data also suggest that folate deficiency may inhibit colorectal carcinogenesis in chronic UC. However, the high mortality observed in the folate-deficient group precludes a definitive conclusion concerning the effect of folate deficiency on UC-associated colorectal carcinogenesis in this model.
Carrier
Julie
J
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Medline
Alan
A
Sohn
Kyoung-Jin
KJ
Choi
Monica
M
Martin
Rochelle
R
Hwang
Stephen W
SW
Kim
Young-In
YI
D000818:Animals; D002471:Cell Transformation, Neoplastic; D003093:Colitis, Ulcerative / Q000209:etiology / Q000517:prevention & control* / Q000662:veterinary; D015179:Colorectal Neoplasms / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004032:Diet; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005492:Folic Acid / Q000494:pharmacology*; D005494:Folic Acid Deficiency / Q000150:complications / Q000662:veterinary; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D001613:beta 2-Microglobulin / Q000235:genetics*
D007376:Interleukin-2; D001613:beta 2-Microglobulin; D005492:Folic Acid