1,25-Dihydroxy-19-nor-vitamin D2, a vitamin D analog with reduced bone resorbing activity In vitro
1,25-Dihydroxy-19-nor-vitamin D(2) (19-norD(2)), a new analog of 1,25(OH)(2)D(3), suppresses parathyroid hormone in renal failure patients and in uremic rats but has less calcemic activity than 1,25(OH)(2)D(3). Although 19-norD(2) has high affinity for the vitamin D receptor and similar pharmacokinetics to those of 1,25(OH)(2)D(3), it has much less bone resorbing activity in vivo. The intrinsic activity of 19-norD(2) on osteoclastogenesis and activation of bone resorption in mouse bone marrow cultures was examined to determine the mechanism involved. 19-norD(2) and 1,25(OH)(2)D(3) (10 nM) were equivalent in stimulating the formation and maintenance of large multinucleated, tartrate-resistant acid phosphatase-positive cells. However, the amount of bone resorbed by osteoclasts stimulated by 10 nM 19-norD(2), as measured by pit-forming assays, was reduced 62% compared with 10 nM 1,25(OH)(2)D(3)-stimulated osteoclasts (P < 0. 05). This difference could not be attributed to enhanced catabolism or to downregulated vitamin D receptor. The rate of degradation of 19-norD(2) in cultures was approximately 20% greater than 1, 25(OH)(2)D(3), not enough to account for the different effects on bone resorption. The VDR levels were identical in cultures that were treated with 19-norD(2) and 1,25(OH)(2)D(3). In summary, 19-norD(2) is less effective than 1,25(OH)(2)D(3) in stimulating mouse marrow osteoclasts to resorb bone. The reason for this difference is not clear but seems to involve the late maturation and/or activation of osteoclasts as the number of pits produced by each tartrate-resistant acid phosphatase-positive cell is reduced under stimulation by 19-norD(2) compared with 1,25(OH)(2)D(3).
Available from: Gary Schwartz
- "One 19-nor analogue, 19-nor-1a,25-dihydroxyvita- min D 2 (paricalcitol, Zemplar, Abbott Laboratories, Chicago, Ill.) is approved in the US for the treatment of secondary hyperparathyroidism in chronic renal failure (Martin et al. 1998). In vitamin D-deficient rats, paricalcitol is 10 to 100 times less active than calcitriol in stimulating intestinal Ca ++ transport or Ca ++ mobilization from bone (Slatopolsky et al. 1997) and has less bone-resorbing activity than calcitriol in vitro (Holliday et al. 2000). Paricalcitol is as effective as calcitriol in its ability to transactivate the vitamin D receptor (VDR) and to inhibit the proliferation of prostate cancer lines and prostate cancer cells in primary culture (Chen et al. 2000). "
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ABSTRACT: 19-Nor-1alpha,25-dihydroxyvitamin D(2) (paricalcitol) is an analogue of 1,25(OH)(2)D(3) with reduced calcemic effects that is approved for the suppression of parathyroid hormone in chronic renal failure. Paricalcitol has recently been reported to have anticancer activity in prostate cancer. In order to explore paricalcitol as a potential agent against leukemia, we tested its effects on HL-60 and U937 leukemia cell lines.
We studied cellular differentiation via expression of CD11b and CD14 surface antigens using flow cytometry, and via the nitroblue tetrazolium (NBT) assay. Cell cycle was analyzed using propidium iodide staining. Apoptosis was assessed with the annexin V assay. Cellular proliferation was determined via colony inhibition on semisolid medium.
Paricalcitol induced the maturation of HL-60 and U937 cells, as shown by increased expression of CD11b differentiation surface antigen. CD14 showed increased expression in HL-60 but not in U937 cells. After exposure to paricalcitol at 10(-8) M for 72 h, the ability of HL-60 cells to reduce NBT was markedly increased. Conversely, U937 cells were unchanged. Paricalcitol inhibited colony formation of both HL-60 and U937 cell lines in semisolid medium after a 10-day incubation (estimated IC(50) of 3x10(-8) M in HL-60 cells and 4x10(-8) M in U937 cells). Paricalcitol at 10(-8) M and 10(-7) M caused a significant dose- and time-dependent increase of apoptosis in HL-60 cells ( P<0.05). In both HL-60 and U937 cells, exposure to 10(-7) M paricalcitol for 72 h increased the number of cells in G(0)/G(1) phase, and decreased the number of cells in S phase.
Paricalcitol inhibits colony formation, induces maturation and causes cell cycle arrest in HL-60 and U937 cells. Additionally, paricalcitol induces apoptosis in HL-60 cells. These findings support the further evaluation of paricalcitol as an antileukemia agent.
Available from: Eduardo Slatopolsky
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ABSTRACT: Secondary hyperparathyroidism (2HPT), a common disorder in patients with chronic renal failure, develops in response to phosphate
retention and low serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol). Replacement therapy with calcitriol or its precursor 1α-hydroxyvitamin D3 (1αOHD3, alfacalcidol) often produces hypercalcaemia, especially when combined with calcium-based phosphate binders. In addition,
these vitamin D compounds can aggravate the hyperphosphataemia in these patients. Several vitamin D analogues have been developed
that retain the direct suppressive action of 1,25(OH)2D3 on the parathyroid glands but have less calcaemic activity, thereby offering a safer and more effective means of controlling
2HPT. 1,25-Dihydroxy-19-norvitamin D2 (19-norD2) and 1α-hydroxyvitamin D2 (1αOHD2) are available in the US and 1,25-dihydroxy-22-oxavitamin D3 (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D3 (1,25(OH)226,27F6 D3, falecalcitriol) have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-norD2 have a wider therapeutic window for suppression of parathyroid hormone (PTH) because of their lower calcaemic and phosphataemic
activities. The low calcaemic activity of OCT has been attributed to its rapid clearance, which prevents sustained effects
on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression and
parathyroid cell growth. The calcaemic activity of 19-norD2 diminishes with the duration of treatment by as yet unknown mechanisms. The lower toxicity of 1αOHD2, compared with 1αOHD3, has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions
of falecalcitriol may also result from an altered metabolism. A clear understanding of the molecular basis for the selectivity
of vitamin D analogues on parathyroid function may allow the design of even more effective analogues.
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ABSTRACT: Patients with chronic renal failure frequently develop secondary hyperparathyroidism, primarily as a result of phosphate retention and low serum 1,25(OH)2D3. Replacement therapy with calcitriol or its synthetic precursor alfacalcidol [1α(OH)D3] often produces hypercalcemia, especially when combined with calcium-based phosphate binders. In addition, the natural vitamin D compounds can exacerbate the hyperphosphatemia in patients with chronic renal failure. This combined increase in calcium and phosphate has been correlated with vascular calcification leading to coronary artery disease, the most common cause of mortality in renal patients.
Several vitamin D analogs have now been developed that retain the direct suppressive action of calcitriol on the parathyroid glands but have less calcemic activity, thereby offering a safer and more effective means of controlling secondary hyperparathyroidism. Maxacalcitol [22-oxa-1,25(OH)2D3] and falecalcitriol [1,25(OH)2-26,27-F6-D3] are currently available in Japan, and paricalcitol [19-nor-1,25(OH)2D2] and doxercalciferol [1α(OH)D2] are available in the US. The mechanisms by which these analogs exert their selective actions on the parathyroid glands are under investigation. The low calcemic activity of maxacalcitol has been attributed to its rapid clearance from the circulation. This prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of parathyroid hormone gene expression. The selectivity of the other analogs is achieved by distinct mechanisms. Understanding how these compounds exert their selective actions on the parathyroid glands will aid in the design of safer, more effective analogs.
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