Stage-specific inhibition of mammary carcinogenesis by 1alpha-hydroxyvitamin D5

Active metabolites of vitamin D are well recognised as cancer chemopreventive and chemotherapeutic agents. However, they are toxic at effective concentrations. Earlier, we reported that a non-toxic analogue of vitamin D, 1alpha-hydroxyvitamin D5(1alpha(OH)D5), inhibited carcinogen-induced mammary lesion formation in mouse mammary organ cultures (MMOC) and in N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinogenesis. In the present study, we determined if 1alpha (OH)D5 action is selective during the initiation or promotion phases in MMOC and in vivo. In MMOC, 1 microM 1alpha (OH)D5 suppressed both ovarian hormone-dependent and -independent mammary lesions by more than 60%. Inhibition of alveolar lesions was observed only during the promotion stage (p=0.0016). In a 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis experiment, 1alpha (OH)D5 (40 microg/kg diet) inhibited cancer incidence by 37.5% (p<0.05) if 1alpha (OH)D5 was present in food during the promotion phase (+1 to end). However, a D5-supplemented diet during the initiation phase (-2 to +1 week) did not provide any protection. These results clearly show, for the first time, that the effects of vitamin D may be mediated selectively during the promotion or progression phases of carcinogenesis.