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Carcinogenesis, Vol. 21, No. 2, 173-178, February 2000
© 2000 Oxford University Press

Molecular Epidemiology and Cancer Prevention

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

Tetsuhide Taniyama, Hideki Wanibuchi, Elsayed I. Salim, Yoshihisa Yano1, Shuzo Otani1, Yoshiki Nishizawa2, Hirotoshi Morii2 and Shoji Fukushima3

First Department of Pathology,
1 Second Department of Biochemistry and
2 Second Department of Internal Medicine, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

In this study we investigated the effects of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] 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)2D3 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)2D3 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)2D3 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)2D3. In experiment 4, using the multicarcinogenic protcol 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)2D3 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)2D3 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)2D3 inhibits colon carcinogenesis specifically, without any enhancement of carcinogenesis in other organs, when administered in the post-initiation phase.

Abbreviations: ACF, aberrant crypt foci; BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; BrdU, 5-bromo-2'-deoxyuridine; COX, cyclooxygenase; DEN, diethylnitrosamine; DHPN, 2,2'-dihydroxy-di-n-propylnitrosamine; DMBDD treatment, combined carcinogen treatment; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; 24R,25(OH)2D3, 24R,25-dihydroxyvitamin D3; DMH, N,N'-dimethylhydrazine; GST-P, glutathione S-transferase placental form; MNU, N-methylnitrosourea; ODC, ornithine decarboxylase; SAT, spermidine/spermine N1-acetyltransferase.


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