The role of vitamin D in colorectal cancer (CRC) prevention is well recognized. Epidemiological evidence demonstrates an inverse relationship between vitamin D, both dietary intake and exposure to sunlight, and risk of developing colon cancer. Similarly, decreased plasma levels of 25-hydroxyvitamin D3 [25(OH)D3] have been shown to correlate with increased polyp formation in distal colons of women. Experimental evidence has found that treatment of animals with the active metabolite of vitamin D, 1,25-dihydroxyvitamin D3, reduces colon tumor burden. However, 1,25(OH)2D3 causes hypercalcemia. In view of this numerous analogs of vitamin D have been synthesized. Yet only a handful of these analogs have been successfully used for the prevention and therapy of colon cancer. In our laboratory we synthesized a novel vitamin D analog, 1a-hydroxy-24-ethyl-cholecalciferol [1cc(OH)D5]. The preliminary results showed that this agent at non-toxic levels significantly decreases the formation of aberrant crypt foci (ACF) by 85% in mice exposed to the carcinogen azoxymethane (AOM). Recently, it has been observed that 1a-hydroxylase, required to convert non-toxic 25(OH)D3 to 1,25(OH)2D3- is present in colonic epithelial cells. This suggests that 25(OH)D3 alone may serve as potential chemopreventive agent. Finally, the role of vitamin D receptor (VDR) remains to be fully elucidated. Our preliminary data indicates that vitamin D's role in CRC chemopreventive activity requires VDR expression, and that aberrant (3Jcatenin may be modified by up- regulation of VDR. Thus, we hypothesize that 25(OH)D3 will serve as a colon chemopreventive agent with its actions mediated primarily via VDR.
Our specific aims are to: (1 A) Determine the dose response of 25(OH)D3 in suppressing the development of AOM-induced ACF and adenocarcinomas in CF-1 mice; (1B) Evaluate the relative efficacy of 25(OH)D3, 1a(OH)D5, and 1,25(OH)2D3 in colon carcinogenesis. For this aim the AOM-induced CRC model will be used; (2) Assess the role VDR, 1a(OH)ase, and 24-hydroxylase in ACF and CRC progression. For these studies an AOM-induced carcinogenesis model using VDR knockout and their wild-type counterparts will be used to evaluate the responsiveness to 25(OH)D3; and (3) Investigate the mediating role of VDR in the wnt/(3-catenin signaling pathway and its relation to vitamin D actions. The studies will provide a rationale for using 25(OH)D3 for the prevention of colon carcinogenesis. ? ? ?
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