POTENT GENE REGULATORY AND ANTIPROLIFERATIVE ACTIVITIES OF 20-METHYL ANALOGS OF 1,25-DIHYDROXYVITAMIN-D-3

The biological active form of vitamin D-3, 1,25-dihydroxyvitamin D-3 ( VD), regulates cellular growth and differentiation. This provides the hormone with an interesting therapeutic potential. However, hypercalce mia is a side effect, which is caused by VD's classical action, the re gulation of calcium homeostasis. This made the need for VD analogues w ith selectively increased cell regulatory properties. Studies with 20- epi analogues pointed out the importance of the carbon-20 position and led to the development of 20-methyl derivatives of VD. In this report the biological properties of the compounds ZK161422 and ZK157202, whi ch are 20-methyl- and 20-methyl-23-ene-analogues, respectively, have b een analyzed in comparison with VD. Both compounds show about 2-fold l ower affinity to the VD receptor (VDR) than VD. However, compared to V D, their antiproliferative effect is up to 30-fold higher on human per ipheral blood mononuclear cells and even up to 300-fold higher on huma n breast cancer MCF-7 cells. Whereas the hypercalcemic effect for ZK15 7202 is also increased 10-fold, ZK161422 has the same calcium-mobilizi ng potency as VD. Moreover, ZK161422, but not ZK157202, showed prefere nce for gene activation from a promoter carrying a VD response element with a palindromic arrangement of two hexameric receptor binding site s spaced by 9 nucleotides (IP9) rather than for activation from a resp onse element formed by a direct repeat spaced by 3 nucleotides (DR3). This observation supports a model, in which promoter selectivity refle cts the selectively increased antiproliferative effect of VD analogues . (C) 1996 Wiley-Liss, Inc.