Monocytic differentiation induced by side-chain modified analogs of vitamin D in ex vivo cells from patients with acute myeloid leukemia.

The differentiation-inducing potential of side-chain modified analogs of vitamins D, compared to the reference compound, 1,25-dihydroxyvitamin D3, was studied in blast cells from patients with acute myeloid leukemia and in cell lines. Analogs PRI-1906 and PRI-1907 showed increased cell-differentiation activities, PRI-1907 even at a very low concentration. Our study revealed a high variability of individual patients' blasts in their susceptibility to vitamin D analogs.

Regulation of Leukemic Cell Differentiation through the Vitamin D Receptor at the Levels of Intracellular Signal Transduction, Gene Transcription, and Protein Trafficking and Stability.

1α,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D) exerts its biological activities through vitamin D receptor (VDR), which is a member of the superfamily of steroid receptors, that act as ligand-dependent transcription factors. Ligated VDR in complex with retinoid X receptor (RXR) binds to regulatory regions of 1,25(OH)(2)D-target genes. 1,25(OH)(2)D is able to induce differentiation of leukemic blasts towards macrophage-like cells.

Opposite regulation of vitamin D receptor by ATRA in AML cells susceptible and resistant to vitamin D-induced differentiation.

Some leukemic cell lines can be driven to differentiate to monocyte-like cells by 1,25-dihydroxyvitamin D(3) (1,25D) and to granulocyte-like cells by all-trans retinoic acid (ATRA). Acute myloid leukemias (AMLs) are heterogeneous blood malignancies characterized by a block at various stages of hematopoietic differentiation and there are more than 200 known chromosome translocations and mutations in leukemic cells of patients diagnosed with AML. Because of the multiplicity in the genetic lesions causing the disease, AMLs are particularly difficult to treat successfully.

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2.

1,25-Dihydroxyvitamin D3 (1,25D) is implicated in many cellular functions including cell proliferation and differentiation, thus, exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D are its potent calcemic and phosphatemic activities. Therefore, synthetic analogs of 1,25D for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced.

Different susceptibilities to 1,25-dihydroxyvitamin D3-induced differentiation of AML cells carrying various mutations.

This study was designed to compare the differentiation-inducing potential of 1,25-dihydroxyvitamin D(3) (1,25D) with some analogs (VDAs) in a panel of acute myeloid leukemia (AML) cell lines and in blast cells isolated from patients with AML. Of the cell lines studied, HL60 proved to be the most sensitive to each of the differentiation-inducing agents when compared to THP-1, NB-4 and U-937 cell lines. Three of the VDAs tested (PRI-1906, PRI-2191 and PRI-2201) were similarly effective as 1,25D in all the cell lines tested.