ABSTRACT The active vitamin D metabolite, 1, 25-dihydroxyvitamin D3, is an important modulator of cellular growth and differentiation in a variety of normal and malignant tissues. The genomic actions of vitamin D3 are mediated through its nuclear receptor (vitamin D receptor - VDR) which is a trans-acting transcriptional factor and a member of the steroid nuclear hormone receptor superfamily of genes. VDR regulates gene expression by binding to vitamin D response elements, which are hexomeric core binding motifs in the promoter regions of target genes. In addition vitamin D may also have non-genomic actions by activating downstream protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways. In vitro, vitamin D3 has cytostatic and cytotoxic effects on cancer cell lines, and can also induce apoptosis, increase the cytotoxic action of macrophages and lymphocytes, and potentiate the cytostatic and cytotoxic effects of TNF and other inflammatory mediators, all of which could contribute to a potential anti-cancer effect. In vivo, vitamin D3 can retard the growth of xenografts of various human cancer cells in nude mice, although its hypercalcaemic effect has prevented its application as a therapeutic agent. Recently, a number of vitamin D analogues have been developed with potent anti-tumour activity in pre-clinical models but with a less hypercalcaemic effect than vitamin D3, and are now undergoing early clinical evaluation. In this article we review the molecular mechanisms of vitamin D receptor action, discuss the preclinical and clinical evaluation of vitamin D analogues, and speculate on the potential contribution of these agents as therapeutic strategies in the management of malignant disease.
Buy this Article
|