Inhibition of Development of N, N′‐Dimethylhydrazine‐induced Rat Colonic Aberrant Crypt Foci by Pre, Post and Simultaneous Treatments with 24R,25‐Dihydroxyvitamin D₃

Abstract

It has recently been reported that new vitamin D3 derivatives can exert inhibitory effects on colon carcinogenesis in rats. In the present study the chemopreventive potential of 24R,25‐dihydroxyvitamin D3 (24ff,25(OH)2vitainin D3) was assessed in a murine model of colon carcinogenesis. In experiment 1, male 6‐week‐old F344 rats were administered N2N‐dimethylhydrazme (DMH) 20 mg/kg s.c. once a week 4 times. The rats were fed 24R,25(OH)2vitaniin D3 at 10 ppm in the diet prior to (pre), together with (simultaneous) or after (post) DMH treatment. Modifying effects were assessed using aberrant crypt foci (ACF), putative preneoplastic lesions, as the end point markers in this model of colon carcinogenesis. After 8 weeks, pre and more markedly simultaneous administration of 24R,25‐(OH)2vitamin D3 was found to have reduced the total numbers of ACF and significantly inhibited the development of foci. After 16 weeks, numbers of foci with ≥4 crypts, which are more likely to progress to tumors, were significantly reduced. The most pronounced inhibition of ACF development was noted in rats fed the 24R,25(OH)2vitaniin D3 after DMH administration. The reduction was particularly marked in the proximal colon. Blood levels of calcium were not significantly increased over the control levels in groups administered DMH and the vitamin. Immunohistochemical staining showed numbers of proliferating cell nuclear antigen‐positive cells to.be lower in the colonic epithelia of rats fed the vitamin D3 metabolite than in the controls. In experiment 2, the effect of 24R,25‐(OH)2vitamin D3 on the alterations in c‐fos, c‐myc and c‐jun oncogene expression in response to DMH administration was examined by northern blot analysis. The early increase in expression of ornithine decarboxylase (ODC) activity was not altered by 24R,25(OH)2vitamin D3. The results suggest that 24R,25(OH)2vitamin D3 is a cancer chemopreventive agent which may suppresses DMH induction of lesions and their subsequent development via an antiproliferative action.

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

“…PhIP is known to induce ACF in different strains of rats in a dosedependent manner, 28 but to a much lower degree than azoxymethane (AOM) 29 or dimethylhydrazine (DMH). 30 Furthermore, lowdose potential of PhIP on the induction of ACF has already been described by Fukushima et al 31 In the present study, the particular focus was on the pathologic examination of practical effects of PhIP at low doses mimicking human exposure levels. For this purpose, we adopted a 2-stage carcinogenesis model featuring initiation with AOM to gain an appreciable tumor yield in the large intestine for quantitative analysis using tumors as endpoints.…”

“…4 crypts) as described previously. 30 For the quantitative analysis, the mucosal area (cm 2 ) of each colonic segment was measured with the aid of a color video image processor (IPAP; Sumica Technos, Osaka, Japan) and all ACF data were expressed as numbers/cm 2 . Thereby, 5 rats were omitted from the effective numbers because colonic areas could not be measured accurately mainly due to perforation.…”

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

“…In the case of the 24R,25-dihydroxyvitamin D 3 analog, studies using rats with chemically induced colonic aberrant crypt foci (early signs of colon cancer) or glandular stomach cancer have suggested that this analog exerts chemopreventive effects (264,265). No rise in serum calcium was seen in former study, but urinary calcium levels were found to be markedly increased in the treated animals, indicating that 24R,25-dihydroxyvitamin D 3 have a narrow therapeutic window.…”

Vitamin D analogues in colon cancer prevention and care

“…Iseki and Kobayashi [43] found signifi cantly reduced gastric hyperplasia and adenocarcinoma and decreased multiplicity in MNNG-challenged animals. Administration of this analogue during or after dimethylhydrazine challenge showed reduced ACF formation and PCNA index in both cases, but it was more marked in the postchallenge group [44]. A complex set of experiments looked at the effects of 24R,25(OH) 2 D 3 on a time point-sensitive, multicarcinogen, multiorgan study of colon cancer in rats [45].…”