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

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.

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.