1α,25-Dihydroxyvitamin D3 [1α,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 1α,25-(OH)2D3 once a week at a dose of 1 µg or less, a tolerable dose from hypercalcemia, dose dependently inhibited tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). When 1 µg of 1α,25(OH)2D3 was applied 30 min before 5 µg 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 µg of TPA (Stage I) was followed by repeated applications of 5 µg of mezerein once a week for 19 weeks (Stage II). When 1α,25(OH)2D3 at 1 µg 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 1α,25(OH)2D3 at Stage I only did not inhibit tumor formation, indicating that 1α,25(OH)2D3 specifically inhibited Stage II promotion. These results are in good agreement with the previous and present findings that 1α,25(OH)2D3 inhibited induction of epidermal omithine decarboxylase by TPA and mezerein. The possibility that 1α,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 1α,25(OH)2D3 alone-treated animals.
Supported in part by a Grant for Cancer Research from the Ministry of Education, Science, and Culture of Japan.