Inhibition of tumor promotion in mouse skin by 1 alpha,25-dihydroxyvitamin D3.
1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25(OH)2D3], a hormonally active form of vitamin D3, was found to inhibit the promotional phase of 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis in female Sencar mice. Topical application of 1 alpha,25-(OH)2D3 once a week at a dose of 1 micrograms or less, a tolerable dose from hypercalcemia, dose dependently inhibited tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). When 1 micrograms of 1 alpha,25(OH)2D3 was applied 30 min before 5 micrograms of TPA, the times required for 50 and 100% tumor incidence were delayed about 2.5 and 7 weeks, respectively, and the number of tumors per mouse was decreased by 25-30%. This inhibitory effect was more pronounced when examined by a two-stage promotion protocol, in which a single application of 5 micrograms of TPA (Stage I) was followed by repeated applications of 5 micrograms of mezerein once a week for 19 weeks (Stage II). When 1 alpha,25(OH)2D3 at 1 micrograms was applied at Stage I + II or Stage II, tumor formation was markedly suppressed, resulting in decrease of about 70-80% in the incidence and 87-90% in the number of tumors per mouse. Application of 1 alpha,25(OH)2D3 at Stage I only did not inhibit tumor formation, indicating that 1 alpha,25(OH)2D3 specifically inhibited Stage II promotion. These results are in good agreement with the previous and present findings that 1 alpha,25(OH)2D3 inhibited induction of epidermal ornithine decarboxylase by TPA and mezerein. The possibility that 1 alpha,25(OH)2D3 suppressed tumor promotion by killing initiated cells rather than inhibiting promotion was ruled out by an experiment in which TPA was applied to the 1 alpha,25(OH)2D3 alone-treated animals.
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate
D009955:Ornithine Decarboxylase; D002117:Calcitriol; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium