Antiproliferative and immunoregulatory actions of vitamin D derivatives on hematological malignancies

The physiological form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has a role in normal hematopoiesis, enhancing monocyte-macrophage differentiation. The focus in this chapter is on the antiproliferative, prodifferentiation, and cell survival effects of vitamin D derivatives (VDDs) studied in various myeloid leukemia cell lines and leukemic blasts ex vivo. The proposed mechanisms and signaling pathways by which VDDs induce cell type-specific and cell context-specific effects are described here. Clinical trials with 1,25(OH)2D3 have been performed for the treatment of preleukemia/myelodysplastic syndrome and acute myeloid leukemia (AML), but the doses effective in vitro cause hypercalcemia in vivo. However, numerous VDDs have been synthesized, which in model systems have reduced calcemic activity but an increased ability to induce cell differentiation and to inhibit proliferation of leukemic cells. The availability of new analogs combined with other differentiating or antiproliferative agents may demonstrate synergistic activity and offer improved therapy for AML.