Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding capacity (Bmax) and the affinity (Kd) of the intestinal vitamin D receptor (VDR) have been studied using mucosa preparations from the duodenum, jejunum and proximal colon of male growing goats which had been kept in a two-factorial (2 x 2) trial on Ca and/or P deficient diets for 9 weeks. This treatment resulted in significant changes of different parameters of Ca and P homeostasis. Irrespective from the level of Ca intake, P depletion caused significant hypophosphatemia with corresponding hypercalcemia. In both Ca depleted groups the calcitriol concentrations in plasma significantly increased by more than 100% in comparison with normal Ca supply. No changes were recorded for plasma calcitriol concentrations in response to P depletion with an adequate Ca supply. Plasma PTH levels were only increased significantly in Ca depletion with adequate P supply. Irrespective of different feeding regimens, the highest Bmax values were found in the jejunum. In all intestinal segments tested, the Bmax values were significantly decreased by P depletion as compared with an adequate P supply. No effects on the Bmax of VDR were observed in response to changes of Ca supply. The Kd values of the VDR were neither affected by different intestinal localizations nor by Ca and/or P depletion. From the present results, it has to be concluded that the physiological relevance of VDR down-regulation may not be related to P homeostasis rather than to Ca homeostasis by minimizing the hypercalcemia induced by P depletion.
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PMID:Binding properties of goat intestinal vitamin D receptors as affected by dietary calcium and/or phosphorus depletion. 749 73

It is now recognized that it is casual exposure to sunlight that provides most humans with their vitamin D requirement. During exposure to sunlight, the high energy ultraviolet B photons (290-315 mm) photolyzes cutaneous stores of 7-dehydrocholesterol to previtamin D3. Once formed, previtamin D3 undergoes a thermal isomerization that results in the formation of vitamin D3. Vitamin D3 is biologically inert and requires successive hydroxylations in the liver and kidney to form its biologically active hormone 1,25-dihydroxyvitamin D3. The major physiologic function of 1,25-dihydroxy-vitamin D3 is to maintain blood calcium in the normal range. It accomplishes this by increasing the efficiency of intestinal calcium absorption and mobilizing stem cells to become osteoclasts which, in turn, remove calcium from the bone. It is now recognized that there are a variety of calcium metabolic disorders that are related to defects in the synthesis and metabolism of vitamin D. Chronic granulomatous disorders are often associated with hypercalciuria and hypercalcemia. The mechanism by which this occurs is that activated macrophages within granulomatous tissue, in an unregulated manner, convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Besides its calcemic activity 1,25-dihydroxyvitamin D3 is a potent antiproliferative factor for cells and tissues that possess its vitamin D receptor. This has clinical utility in that 1,25-dihydroxyvitamin D3 and its analogs have been successfully used for the treatment of the hyperproliferative skin disease psoriasis.
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PMID:Defects in the synthesis and metabolism of vitamin D. 758 27

The present study was undertaken to clarify the pharmacokinetics of 22-oxa-1,25-dihydroxyvitamin D3 (22-oxa-1,25-(OH)2D3, OCT), a vitamin D3 analogue with little calcemic activity, and its effect on the transcription of parathyroid hormone-related peptide (PTHRP) gene in nude mice bearing a human carcinoma (FA-6) associated with humoral hypercalcemia. FA-6 tumor expressed vitamin D receptor (VDR) mRNA, and its nuclear extract contained a specific and saturable 1,25-(OH)2D3 binding activity. Although [3H]OCT administered intravenously into FA-6 tumor-bearing nude mice was cleared from the circulation more rapidly than [3H]1,25-(OH)2D3, the uptake of [3H]OCT into the tumor tissue, relative to the radioactivity in the circulation, was greater than that of [3H]1,25-(OH)2D3. Intravenous or oral administration of OCT reduced the steady-state levels of PTHRP mRNA in FA-6 tumor, and nuclear run-off assays demonstrated that the effect of OCT on PTHRP gene expression occurred at a transcriptional level. RNase mapping analysis revealed that both upstream and downstream promoters of the human PTHRP gene were down-regulated by OCT. Finally, OCT exerted a preventive as well as therapeutic effect on cancer-associated hypercalcemia with a marked prolongation of the survival time in tumor-bearing animals. These results suggest that OCT is effectively taken up by a VDR-positive human carcinoma in vivo and has a therapeutic potential for cancer-associated hypercalcemia through suppression of PTHRP gene transcription.
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PMID:Evidence for the uptake of a vitamin D analogue (OCT) by a human carcinoma and its effect of suppressing the transcription of parathyroid hormone-related peptide gene in vivo. 779 77

The cholecalciferol analogues 1(S),3(R)-dihydroxy-20(R)-[3'(S)-cyclopropyl-3'-hydroxyprop-1'(E)- enyl]-9,10-secopregna-5(Z),7(E),10(19)-triene (calcipotriol, MC 903), 1(S),3(R)-dihydroxy-20(R)-[3'-ethyl-3'-hydroxy- pentoxy]-9,10-secopregna-5(Z),7(E),10(19)-triene (KH 1060) and 1(S),3(R)-dihydroxy-20(R)-[5'-ethyl-5'-hydroxy-hepta- 1',3'(E)-diene-1'-yl]-9,10-secopregna-5(Z),7(E),10(19)-triene (EB 1089) have been modified in the side chain to increase their effects on cell differentiation and proliferation and to reduce the risk of inducing hypercalcemia. The effects of these analogues were tested on FRTL-5 cells, a strain of continuously growing and well-differentiated rat thyroid cells. FRTL-5 cells express a normal vitamin D receptor (VDR), and 1,25-(OH)2D3 potently attenuates the thyrotropin (TSH) stimulated production of the intracellular signalling molecule 3',5'-cyclic adenosine monophosphate (cAMP), iodide uptake and cell growth of these cells. These effects were also induced by the cholecalciferol analogues after 4 days of incubation. KH 1060 was the biologically most potent of the analogues and, compared to KH 1060, the IC50 values were 1.2-, 2.7- and 14-fold higher when 1,25-(OH)2D3, EB 1089 and MC 903, respectively, were used for the displacement of receptor bound [3H]1,25-(OH)2D3. As indicated by their VDR binding, 1,25-(OH)2D3 and EB 1089 were equipotent inhibitors of the TSH stimulated adenylyl cyclase activity, iodide uptake and FRTL-5 cell growth. The analogue MC 903 was the second most potent inhibitor of cell growth in spite of expressing the lowest affinity for the VDR and the weakest inhibition of TSH-stimulated adenylyl cyclase activity and iodide uptake. In conclusion, the biological effects of these cholecalciferol analogues in rat thyroid FRTL-5 cells seem to be mainly determined by their binding affinity for the VDR, although non-genomic effects can not be excluded.
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PMID:Vitamin D receptor binding and biological effects of cholecalciferol analogues in rat thyroid cells. 804 43

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.
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PMID: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. 839 73

1,25(OH)2D3 promotes differentiation and has an antiproliferative effect in a variety of cell lines derived from the immunohaematopoetic system. alpha-Calcidol which is metabolised to 1,25(OH)2D3 has been shown to produce tumour regression in follicular low grade non-Hodgkin's lymphoma (NHL) and the dose limiting toxicity is hypercalcaemia. The cellular action of 1,25(OH)2D3 is mediated by binding to an intracellular protein, the vitamin D receptor (VDR). We have evaluated the activity of 1,25(OH)2D3 and its non-calcaemogenic analogue MC903 in the SU-DHL4 and SU-DUL5 B cell lines which carry the 14;18 translocation characteristic of follicular NHL, and also the expression of the VDR in a range of B cell NHLs. Both agents induced differentiation and had an antiproliferative effect on the SU-DHL4 and SU-DUL5 cell lines. However this occurred at a relatively high concentration (10(-7) M) which exceeds the physiological concentration of 1,25(OH)2D3 by approximately 10(3)-10(4)-fold. Expression of the VDR was low in each cell line and in the low grade lymphoma tumour samples. To account for the observed clinical response to 1 alpha OHD3 (alpha-calcidol) in follicular NHL a network is suggested whereby 1,25(OH)2D3 modulates the activity of CD4+T cells which have previously been shown to promote follicle centre cell proliferation. Vitamin D3 analogues may enable serum levels to be achieved which produce a direct action on follicular lymphoma cells without disturbing calcium metabolism.
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PMID:The effect of 1,25-dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma. 839 90

Vitamin D has been discovered at the beginning of this century. 7-Dehydrocholesterol is converted to vitamin D3 in the skin and after several hydroxylations it is further converted to the active hormonal form, 1 alpha,25-(OH)2D3. Vitamin D stimulates the absorption of calcium and phosphate and is an essential link in bone resorption and formation and calcium metabolism. 1 alpha,25-(OH)2D3 acts through a vitamin D receptor. These receptors are not only present in clinical target organs (kidney, gut, liver) but can also be found in a wide variety of "non-classical" tissues (keratinocytes, cells belonging to the immune system). Moreover, numerous cells (keratinocytes, macrophages) can locally synthetize or can be induced to synthetize 1 alpha,25-(OH)2D3 and these cells are responsive to its action. When these data are combined, a possible paracrine function of 1 alpha,25-(OH)2D3 can be suspected. Via this paracrine function 1 alpha,25-(OH)2D3 can suppress the cellular and humoral immunity. Based on the discovery of these effects on immune cells in vitro it became clear that 1 alpha,25-(OH)2D3 might be an interesting molecule to prevent autoimmune diseases and organ transplantation. This has already been shown in several animal models (Heymann nephritis, diabetes mellitus, experimental allergic-encephalomyelitis, lupus). 1 alpha,25-(OH)2D3 demonstrates however some side-effects (hypercalciuria, hypercalcemia, bone resorption) and for this reason 1 alpha,25-(OH)2D3-analogs are developed with dissociated effects i.e. an activity profile that allows a specific action on non-classical tissues without calcemic effects. Some chemical modifications of the side chain, A and/or CD-ring results in "superanalogs" with 10 to 100-fold more activity on cell differentiation and the immune system then 1 alpha,25-(OH)2D3 but with less calcemic activity in vivo. These biological effects can be explained by differences in pharmacokinetics (low affinity for the plasma vitamin D-binding protein and short extracellular half-life) and increased intracellular activation and gen transactivation. Preclinical research must still be done to select the most potent superanalogs and to find the exact protocols for the prevention and treatment of autoimmune diseases and rejection of transplanted organs.
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PMID:[Immune modulation by vitamin D analogs in the prevention of autoimmune diseases]. 857 69

The variability of different primary tumors in the susceptibility to metastatic bone disease is poorly understood. Factors that determine the viability of metastatic cells are also poorly understood, but may depend in part upon gene expression of PTHrP and the vitamin D receptor. In contrast, much more is known of the manner in which metastatic disease affects bone remodeling to induce osteolytic bone disease. Mechanisms include a generalized increase in activation frequency at sites close to metastatic tissue, an imbalance between the amount of bone formed and that resorbed within resorption cavities, and uncoupling of bone formation from bone resorption. The greatest morbidity from metastatic bone disease arises from osteolytic disease and gives rise to hypercalcemia, bone pain, and fractures. Because osteolysis is primarily mediated by the activation of osteoclasts, there has been a great deal of interest in the use of agents which primarily affect bone metabolism to alter the natural history of metastatic bone disease. Nonsteroidal antiinflammatory agents and cytotoxic agents are capable of inducing responses in bone, but are limited by their toxicity when effective doses are utilized. The use of calcitonin in the long-term suppression of osteolysis has also been disappointing. The bisphosphonates are, however, capable of inducing sustained decreases in osteoclast activity and numbers in patients with osteolytic bone disease. There are now several studies which have examined the effects of the bisphosphonates on skeletal morbidity in breast cancer. Both clodronate and pamidronate decrease the incidence of hypercalcemia, bone pain, and pathological fractures, but do not significantly alter mortality.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bone and cancer: pathophysiology and treatment of metastases. 857 90

The effects on renal and intestinal calbindin-D of vitamin D3 metabolites and synthetic 20-epi-vitamin D3 analogs with different calcemic actions were examined in Wistar rats. The compounds were administered intraperitoneally once daily for 5 days. The dosages of the metabolites were 1,25-(OH)2D3 0.01, 0.05, 0.1, and 0.4 microg/kg x d, 24,25-(OH)2D3 0.1, 1 and 10 microg/kg x d, and 25-(OH)D3 10 and 400 microg/kg x d. The dosage of the synthetic analogs were MC903 0. 1, 10, and 100 microg/kg x d, EB1213 0.1 and 10 microg/kg x d, KH1060 0.1 and 0.4 microg/kg x d, and GS1725 0.01 and 0.1 microg/kg x d. Two control groups had either vehicle alone or no treatment. N = 8 in each group. 1,25-(OH)2D3 increased renal and intestinal calbindin-D levels, induced hypercalcemia, and suppressed plasma PTH and magnesium concentrations. 24,25-(OH)2D3 increased intestinal calbindin-D9k and plasma calcium, but had no effect on renal calbindin-D28k, plasma PTH, and magnesium. The dosage of 24, 25-(OH)2D3 that was required to increase plasma calcium was larger than the dosage required to increase intestinal calbindin-D9k. 25-(OH)D3 did not change the calcium metabolic parameters. MC903, a low calcemic analog with a relative high affinity for the vitamin D receptor and a short half-life, increased renal calbindin-D28k without increasing ionized calcium or intestinal calbindin-D9k. EB1213, an analog with a reduced calcemic action and short half-life, increased renal calbindin-D28k and ionized calcium without increasing intestinal calbindin-D9k. The effect of the high calcemic vitamin D analogs KH1060 and GS1725 on calbindin-D was directly related to their calcemic activity. In conclusion, these results demonstrate that 24,25-(OH)2D3 increases intestinal calbindin-D9k, but has no effect on renal calbindin-D28k, that low calcemic analogs may increase renal calbindin-D28k without increasing intestinal calbindin-D9k, and that the effect of high calcemic analogs on calbindin-D is directly related to their calcemic activity.
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PMID:Effect of vitamin D metabolites and analogs on renal and intestinal calbindin-D in the rat. 884 4

The variability of different breast cancers in the susceptibility to metastatic bone disease is poorly understood. Factors that determine the viability of metastatic cells are also poorly understood, but may depend in part upon gene expression of PTHrP and the vitamin D receptor. In contrast, much more is known of the manner in which metastatic breast disease affects bone remodelling to induce osteolytic bone disease. Mechanisms include a generalized increase in activation frequency at sites close to metastatic tissue, an imbalance between the amount of bone formed and that resorbed within resorption cavities, and uncoupling of bone formation from bone resorption. The greatest morbidity from metastatic bone disease arises from osteolytic disease and gives rise to hypercalcaemia, bone pain and fractures. Since osteolysis is primarily mediated by the activation of osteoclasts, there has been a great deal of interest in the use of agents which primarily affect bone metabolism to alter the natural history of metastatic bone disease. Non-steroidal anti-inflammatory agents and cytotoxic agents are capable of inducing responses in bone, but are limited by their toxicity when effective doses are utilized. The use of calcitonin in the long-term suppression of osteolysis has also been disappointing. The bisphosphonates are, however, capable of inducing sustained decreases in osteoclast activity and numbers in patients with osteolytic bone disease. There are now several studies which have examined the effects of the bisphosphonates on skeletal morbidity in breast cancer. Both clodronate and pamidronate decrease the incidence of hypercalcaemia, bone pain and pathological fractures, but do not significantly alter mortality. Given, however, the unchanging survival in patients with metastatic bone disease, significant improvements in the quality of remaining life is an important therapeutic effect.
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PMID:Rationale for the use of bisphosphonates in breast cancer. 914 69


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