Chemopreventive effect of a vitamin D3 analog, alfacalcidol, on colorectal carcinogenesis in mice with ulcerative colitis

Abstract

An increased incidence of colorectal carcinoma is known to occur in patients with ulcerative colitis (UC), which displays a cycle of recurrence-remission in the colorectal mucosa. Repeated oral doses of 3% dextran sulfate sodium subsequent to a single intraperitoneal injection of azoxymethane induced a chronic UC resulting in an increased incidence of high-grade dysplasia and submucosal-invasive adenocarcinomas in the mouse colorectum. The active form of vitamin D(3) is a calcium-regulating hormone that increases serum calcium levels and intestinal calcium absorption. It has been reported that there is an inverse correlation between serum levels of the active metabolite of vitamin D and colorectal carcinoma stage. The features of the colitis induced in this animal model are very similar to the UC in patients in terms of both clinical and histological characteristics. Treatment with a vitamin D(3) analog, alfacalcidol, in mice prevented colitis and carcinogenesis; this is shown by inhibition of the decrease in colorectal length and inhibition of the increased incidence of colorectal dysplasia, with a reduction in the mRNA expression of the DNA-synthesizing enzyme, thymidine kinase, in colorectal tissues.