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)(2)D-3 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)(2)D-3 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)(2)D-3 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)(2)D-3, namely hypercalcemia, soft tissue calcification and nephrocalcinosis. As a consequence, several analogs of 1 alpha,25(OH)(2)D-3 have recently been identified and are discussed in this paper for consideration as possible chemotherapeutic agents for acute promyelocytic leukemia, breast, colon, and prostate cancer, or as immunosuppressive agents with possible beneficial structure-activity profiles for use in cardiac allografts, autoimmune graft rejection, lupus erythematosus and psoriasis. (C) 1995 Wiley-Liss, Inc.