ABSTRACT

The active form of vitamin D, 1,25-dihydroxy vitamin D₃ (1,25(OH)₂D₃) has been shown to possess many properties unrelated to its classical functions in the control of bone and mineral metabolism. The observation that a high proportion of breast tumour biopsy specimens contain receptors for 1,25(OH)₂D₃ and that the growth of cultured human breast caner cells is inhibited in the presence of this vitamin D metabolite have prompted suggestions that vitamin D derivatives might have potential as therapeutic agents in this and other malignancies. Research with new synthetic analogues clearly shows the possibility of developing vitamin D analogues with enhanced modulatory effects on the non-classical actions of 1,25(OH)₂D₃. An important aim in developing new vitamin D compounds as therapeutic agents in malignancy is separation of hypercalcaemic from anti-proliferative actions. Evaluation of the profile of activity of newer compounds indicates that this aim has, at least in part. been achieved. The analogue EB 1089, when tested in rats to assess its effects on calcium handling. is far less potent than 1,25(OH)₂D₃, despite showing strong, direct effects on growth and differentiation. This compound causes striking regression of experimental mammary tumours, exerting effects that are comparable to the anti-oestrogren tamoxifen.

Tumour regression occurs when the rate of cell death is greater than the rate of cell proliferation and more recent studies have shown that induction of apoptosis may be a feature of the anti-tumour effects of certain vitamin D analogues. Mechanisms by which vitamin D analogues promote apoptosis may involve suppression of cell survival signals, such as insulin-like growth factor-I (IGF-I), induction of genes that stimulate apoptosis or potentiation of other signals leading to cell death such as tumour necrosis factor-α (TNF-α).