The vitamin D Endocrine system: manipulation of structure-function relationships to provide opportunities for development of new cancer chemopreventive and immunosuppressive agents.

Biological responses mediated by vitamin D occur as a consequence of the integrated actions of the vitamin D endocrine system. The vitamin D endocrine system is characterized by the sequential two-step metabolism of vitamin D to 1 alpha,25(OH)2D3 by the liver and kidney, and by the ability to generate biological responses in over 30 target tissues through nuclear receptor (nVDR) regulation of gene transcription and nongenomic pathways. It is now clear that the vitamin D endocrine system embraces many more target tissues than simply the intestine, bone and kidney. Notable additions to this list of tissues containing the nVDR include pancreatic B cells, pituitary gland, breast tissue, placenta, lymphocytes, keratinocytes, colon, and prostate, as well as many cancer cell lines. In addition to the classical actions of 1 alpha,25(OH)2D3 on mediating calcium homeostasis, this seco steroid has been identified as a potent stimulator of cell differentiation as well as an inhibitor of proliferation. Over the past decade at least 400 analogs of 1 alpha,25(OH)2D3 have been chemically synthesized and their biological properties systematically explored in a variety of assays which quantified both their calcemic effects and cell differentiating potential. The objective has been to identify new analogs devoid of the classical calcemic consequences of high doses of 1 alpha,25(OH)2D3, namely hypercalcemia, soft tissue calcification and nephrocalcinosis.(ABSTRACT TRUNCATED AT 250 WORDS)