The potent anti-proliferative effect of 20-epi analogues of 1,25 dihydroxyvitamin D3 in human breast-cancer MCF-7 cells is related to promoter selectivity.
The hormone 1,25-dihydroxyvitamin D3 (VD) has a potential use as an anti-tumor agent, but its clinical applications are restricted by its strong calcemic activity. This has led to the development of VD analogues with selectively increased growth-inhibitory activity. One of the most potent analogues is KH1060, which is a 20-epi-22-oxa-derivative of VD. In human breast cancer MCF-7 cells, we studied the growth-inhibitory activities of a set of 8 analogues that cover conservative structural changes from 20-epi-VD (MC1288) to KH1060. In the same cellular system, we analyzed the potential of these 8 analogues to stimulate reporter gene activity driven by a recently discovered novel-type VD response element. We found that this VD response element is more appropriate than classical VD response elements to correlate anti-proliferative effects of VD analogues with their gene-regulatory properties.
Mørk Hansen
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Department of Biochemistry, LEO Pharmaceutical Products, Bellerup, Denmark.
Danielsson
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Carlberg
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D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D018167:Receptors, Calcitriol / Q000737:chemistry; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; C074279:KH 1060; D002117:Calcitriol; D002118:Calcium