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Medline ® Abstract for Reference 13

of 'Hypercalcemia of malignancy: Mechanisms'

22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T cell lymphotrophic virus, type I-infected T cells.
Inoue D, Matsumoto T, Ogata E, Ikeda K
J Biol Chem. 1993;268(22):16730.
Human T cell lymphotrophic virus, type I (HTLV-I)-infected T cells overproduce parathyroid hormone-related peptide (PTHRP) and cause hypercalcemia in patients with adult T cell leukemia. The present study was undertaken to test whether 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and its noncalcemic analogue, 22-oxa-1,25-(OH)2D3 (OCT), could suppress cell proliferation and PTHRP gene expression in an HTLV-I-infected T cell line, MT-2. OCT as well as 1,25-(OH)2D3 inhibited the proliferation of MT-2 cells in a time- and dose-dependent manner. Cell cycle analysis revealed that OCT, like the parent compound, caused a transition delay of cells through the G1 phase. OCT and 1,25-(OH)2D3 decreased the steady state levels of PTHRP mRNA, and nuclear runoff assays demonstrated that the effect of OCT occurred at a transcription level. As a result, OCT caused a reduction in PTHRP concentrations in the conditioned medium by approximately 50%. OCT inhibited not only the basal secretion but also the stimulation of PTHRP secretion by interleukin-2 or cAMP, which we had identified as two important stimulators. Northern blot analysis and the specific uptake of [3H]1,25-(OH)2D3 revealed unexpectedly that the vitamin D receptor was abundantly expressed in MT-2 cells. These results suggest that OCT, as well as 1,25-(OH)2D3, has the potential to suppress both cell proliferation and PTHRP gene expression through binding to the vitamin D receptor overexpressed in HTLV-I-infected T cells.
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Japan.