Chemopreventive effect of 24R,25-dihydroxyvitamin D3 in N,N'-dimethylhydrazine-induced rat colon carcinogenesis

Abstract

In this study we investigated the effects of 24R,25-dihydroxyvitamin D(3) [24R,25(OH)(2)D(3)] on N,N'-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. For experiments 1 and 2, 50 F344 male, 6-week-old rats were divided into five groups in each experiment. Animals were given s.c. injections of DMH once a week for 4 weeks. Those in groups 1-5 were given 24R,25(OH)(2)D(3) in the diet (10, 5, 2.5, 1.25 or 0 p.p.m., respectively) during the post-initiation stage in experiment 1 and during the initiation stage in experiment 2. At termination, the numbers of aberrant crypt foci (ACF) in the rat colonic mucosa were decreased dose-dependently in rats treated with 24R,25(OH)(2)D(3) during the post-initiation stage, but not in the initiation stage. For experiment 3, 15 male, 9-week-old rats were divided into three groups and given 24R,25(OH)(2)D(3) in the diet (10, 5 or 0 p.p.m.). Animals were injected with 5-bromo-2'-deoxyuridine (BrdU) i.p. 1 h before death to examine DNA synthesis in the colon mucosa. BrdU labeling indices were decreased dose-dependently in colonic crypts of rats treated with 24R, 25(OH)(2)D(3). In experiment 4, using the multicarcinogenic protocol we could analyze our data with respect to not only one separate organ, but at the organism level. Sixty-eight male, 6-week-old rats were treated with DMH, N-methylnitrosourea, 2, 2'-dihydroxy-di-n-propylnitrosamine, diethylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine in weeks 1-4 and were then given 24R,25(OH)(2)D(3) in the diet (5, 1 or 0 p.p.m.) throughout weeks 5-30. Examination of the development of tumors and preneoplastic lesions in various organs revealed that 24R, 25(OH)(2)D(3) inhibited colonic tumor development significantly but exerted no effects on tumor induction in other organs. In conclusion, these results strongly indicate that 24R,25(OH)(2)D(3) inhibits colon carcinogenesis specifically, without any enhancement of carcinogenesis in other organs, when administered in the post-initiation phase.

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia

“…Moreover, both serum levels of vitamin D 3 at the high end of the physiological range 21,22 and consumption of polyphenol-rich diets are consistent with lower risk of certain cancers. 32,33 This is supported by the findings that both VDDs [67][68][69] and rosemary extract and its purified components [56][57][58] suppressed experimental carcinogenesis. Thus, it seems plausible to hypothesize that these compounds may also cooperate in their chemopreventive action.…”

Dairy products and colorectal cancer. A review of possible mechanisms and epidemiological evidence

“…Experimental studies suggest that vitamin D may inhibit cell proliferation (Shabahang et al, 1994;Cross et al, 1992;Wallach et al, 1966;Taniyama et al, 2000). The cell growth inhibitory properties of the vitamin appear to be related to the concentrations of vitamin D receptors on the cell surface rather than vitamin D concentrations.…”

Lack of Chemoprevention or Promotion Effects of Docosahexaenoic Acid on Small Intestine, Colon, Liver, Lung, Thyroid, Esophagus, Kidney, and Forestomach Carcinogenesis in a Rat Medium-Term Multi-Organ Carcinogenesis Model

“…The reason for the discrepancy with the many previous studies which showed chemopreventive effects on colon carcinogenesis and ACF development [1][2][3][4]27,31,32 , may be due to the different number of treatment times per week. DHA was injected five times a 20,21,23,33 incidences of colon tumor development have been reported to range from 10 to 80%, therefore the figure of 10% achieved in the present study was relatively low. Thus, one reason for the lack of obvious influence of DHA could have been due to weak initiation.…”

“…Therefore, we thought it important to investigate the difference in the modifying effects on carcinogenesis of DHA-E and DHA-TG. In the present study, we investigated the post-initiation-phase modifying activity of DHA-E and DHA-TG at the whole organ level using a rat medium-term multi-organ carcinogenesis model developed in our laboratory 8,15,19,20 . Furthermore, a tocopherol group was included as a comparative control.…”