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)

Primary hyperparathyroidism is the third most frequent endocrine disorder. The condition required for diagnosis is inappropriately elevated secretion of parathyroid hormone (PTH) with respect to calcemia. Most often, the disease is due to a parathyroid adenoma, i.e. a monoclonal benign parathyroid tumor, less often to a parathyroid hyperplasia. The main tumorogenic mechanisms currently proposed are a DNA rearrangement in the PTH locus (transposition of the PTH promoter upstream to Cyclin D1/PRAD 1 gene) and a mutation of the gene responsible for multiple endocrine neoplasia type I. The clinical presentation has strikingly evolved towards a milder, asymptomatic form, frequently diagnosed on systematic screenings. Though the mechanism of hypercalcemia is better understood, several hypothesis are still being considered about the regulation of tumoral PTH secretion: the role of the expression of calcium-receptor in parathyroid gland cells, vitamin D receptor and estrogen receptor polymorphisms, etc. Surgery is still advised for symptomatic forms of the disease, either because of a bone involvement, or because of an evolutive nephrolithiasis. In the near future, the new calcium-receptor agonists could be a relevant therapeutic approach.
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PMID:[Primary hyperparathyroidism]. 1111 7

Vitamin D, parathyroid hormone (PTH), and parathyroid hormone-related peptide (PTHrP) are major regulators of calcium metabolism and vitamin D can also reduce the growth of normal cells and tumor cells. PTHrP and PTH act via a common membrane receptor (PTHR). The mouse PTHR is regulated by a kidney-selective upstream promoter P(1) and ubiquitous downstream promoter P(2). In vitro and in vivo 1,25(OH)(2)D can inhibit PTHR expression in bone but not cartilage by downregulating transcription via P(2). Gene transcription of PTHrP per se can also be downregulated by 1,25(OH)(2)D and by low calcemic vitamin D analogs. This inhibitory effect may reduce the hypercalcemia caused by overproduction of PTHrP by tumor cells. In a malignant keratinoctye cell line, phosphorylation of the retinoid X receptor alpha occurs through the activated Ras-MAP kinase pathway and results in attenuated trans-activation by the vitamin D receptor, its heterodimeric partner. This decreases the growth-inhibitory efficacy of 1,25(OH)(2)D. Studies of the capacity of vitamin D to alter PTHrP production and action and of its anti-proliferative effects can, therefore, shed important light on basic mechanisms controlling these events, and may also have major implications for clinical medicine and therapeutics.
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PMID:Studies of the effects of 1,25-dihydroxyvitamin D on skeletal and calcium homeostasis and on inhibition of tumor cell growth. 1138 62

Numerous in vitro and in vivo observations, demonstrating that 1,25-dihydroxyvitamin D(3) is a potent inhibitor of tumor cell growth, provided the rationale for using this seco-steroid hormone to treat patients with leukemia and various types of cancer. However, the therapeutic efficacy of systemically applied vitamin D analogs for treating cancer has not yet fulfilled its promise. A main reason for these disappointing results is that the use of systemically applied vitamin D analogs is limited by severe side effects, mostly hypercalcemia, at the supraphysiological doses needed to reach clinical improvement. New concepts for the development of cancer treatment strategies that are based on the use of vitamin D(3) compounds are discussed in this manuscript. At the moment, different strategies that may enable the application of vitamin D analogs for the treatment of various malignancies, including malignant skin tumors, are employed. It has been shown that certain vitamin D analogs differ in their intracellular metabolism, nongenomic actions, pharmacokinetics, interaction with the vitamin D binding protein (DBP) or the vitamin D receptor (VDR). Several of these new concepts are based on recent laboratory results demonstrating that VDR requires heterodimerisation with additional nuclear cofactors such as the retinoid-X receptor (RXR) for sufficient DNA-binding or are based on new findings in the metabolism of vitamin D. Taken together, these new strategies hold promise that analogs of 1,25-dihydroxyvitamin D(3) may herald a new era in the treatment of various malignancies, including skin cancer.
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PMID:Will analogs of 1,25-dihydroxyvitamin D(3) (calcitriol) open a new era in cancer therapy? 1144 Dec 91

The hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), the active form of vitamin D3, is an important regulator of calcium homeostasis, exerts antiproliferative effects on various cell systems and can induce differentiation in some kinds of hematopoietic cells. These effects are triggered by its receptor, vitamin D receptor (VDR), a phosphoprotein member of the nuclear receptor superfamily, which functions as a transcriptional factor. VDR binds as a heterodimer with retinoid X receptor (R X R) to hexameric repeats, characterized as vitamin D-responsive elements present in the regulatory region of target genes such as osteocalcin, osteopontin, calbindin-D28K, calbindin-D9K, p21WAF1/CIP1, TGF-beta2 and vitamin D 24-hydroxylase. Many factors such as glucocorticoids, estrogens, retinoids, proliferation rate and cell transformation can modulate VDR levels. VDR is expressed in mammary tissue and breast cancer cells, which are potential targets to hormone action. Besides having antiproliferative properties, vitamin D might also reduce the invasiveness of cancer cells and act as an anti-angiogenesis agent. All of these antitumoral features suggest that the properties of vitamin D could be explored for chemopreventive and therapeutic purposes in cancer. However, hypercalcemia is an undesirable side effect associated with pharmacological doses of 1,25-(OH)2D3. Some promising 1,25-(OH)2D3 analogs have been developed, which are less hypercalcemic in spite of being potent antiproliferative agents. They represent a new field of investigation.
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PMID:Antiproliferative effects of 1,25-dihydroxyvitamin D3 on breast cells: a mini review. 1174 8

Previously we have shown that dexamethasone (DEX) enhances the antitumor activity and ligand binding of the active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)), in the murine squamous cell carcinoma model SCC VII/SF. DEX also reduces the hypercalcemia toxicity of 1,25-D(3) treatment. However, the mechanism of the enhanced antitumor activity has not been defined. Here, we demonstrate that both cell cycle arrest and apoptosis were enhanced by DEX, effects that were inhibited by RU486. We also demonstrate that vitamin D receptor (VDR) protein levels were increased by the combination of 1,25-D(3) and DEX above the level observed with 1,25-D(3) treatment alone, whereas protein levels of the heterodimeric partner of VDR, retinoid X receptor, were lower for the combination than for 1,25-D(3) alone. Glucocorticoid receptor protein levels and ligand binding were increased by 1,25-D(3) but not by the combination. Treatment with the combination of 1,25-D(3) and DEX did not result in greater activation of a vitamin D response element-reporter than 1,25-D(3) alone or of a glucocorticoid response element-reporter than DEX alone. Nevertheless, the levels of phospho-Erk1/2 and phospho-Akt, signaling molecules that are modulated in 1,25-D(3)-treated squamous cell carcinoma cells, were reduced by the combination of 1,25-D(3) and DEX more than by either agent alone. These trends were also observed in vivo. Our results suggest the involvement of the Erk and Akt signaling pathways in the antiproliferative effects of the combination of 1,25-D(3) and DEX and that phospho-Erk1/2 and phospho-Akt may be useful markers of response to this combination.
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PMID:Combination of 1alpha,25-dihydroxyvitamin D(3) with dexamethasone enhances cell cycle arrest and apoptosis: role of nuclear receptor cross-talk and Erk/Akt signaling. 1175 17

The cytokine gamma interferon (IFN-gamma) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-gamma induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-gamma-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-gamma and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-gamma action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-gamma/Stat1-induced transcription. This novel 1,25D-IFN-gamma cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.
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PMID:Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. 1190 70

Exposure of leukemia cells to the physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3) normalizes their phenotype to cells that resemble mature monocytes. One of the earliest detectable events in this process is an upregulation of the nuclear receptor for 1,25D3, the vitamin D receptor (nVDR). In contrast, the novel analog of 1,25D3, 1,25-dihydroxy-5,6 trans-16-ene-vitamin D3 (5,6-16D3), which has recently been reported to have low calcium-mobilizing activity in vivo, rapidly induced the expression of CD14, CD11b, and monocyte-specific esterase (MSE), classical markers of the mature monocyte, but upregulated nVDR expression less than 1,25D3. This upregulation was shown to be the result of altered degradation of the nVDR protein, while the levels of nVDR mRNA were constant. Knock-out of nVDR transcriptional activity by a decoy VDRE double-stranded deoxyoligonucleotide, markedly abrogated 1,25D3-induced differentiation, but incompletely inhibited 5,6-16D3-induced differentiation. These findings suggest that the unique ability of 5,6-16D3 to induce cell differentiation but not systemic hypercalcemia, may be due to the activation of pathways which initiate differentiation independently of nVDR.
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PMID:Signaling of monocytic differentiation by a non-hypercalcemic analog of vitamin D3, 1,25(OH)2-5,6 trans-16-ene-vitamin D3, involves nuclear vitamin D receptor (nVDR) and non-nVDR-mediated pathways. 1206 63

Epidemiologic data suggest that low exposure to vitamin D or 1alpha,25-dihydroxycholecalciferol (calcitriol) increases the risk of prostate cancer. Calcitriol, a central factor in bone and mineral metabolism, is also a potent antiproliferative agent in a wide variety of malignant cell types. We have demonstrated that calcitriol has significant antitumor activity in vitro and in vivo in prostate and squamous cell carcinoma model systems. Calcitriol, in these models, induces a significant G0/G1 arrest and modulates p21(Waf1/Cip1) and p27(Kip1), the cyclin-dependent kinase inhibitors. Calcitriol induces poly (adenosine diphosphate-ribose) polymerase cleavage, increases bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs; also known as extracellular signal-related kinase [ERK] 1/2) and phosphorylated Akt, induces caspase-dependent mitogen-activated protein kinase kinase (MEK) cleavage and upregulation of MEK kinase-1, all potential markers of the apoptotic pathway. We also have demonstrated that dexamethasone (dex) potentiates the antitumor effect of calcitriol through effects on the vitamin D receptor and decreases calcitriol-induced hypercalcemia. We initiated phase 1 and phase 2 trials of calcitriol, either alone or in combination with carboplatin, paclitaxel, or dex. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the maximum tolerated dose (MTD) is unclear, and dex or paclitaxel appear to ameliorate hypercalcemia. Studies continue to define the MTD of calcitriol on this intermittent schedule, either alone or with other agents, and to evaluate the mechanisms of calcitriol effects in prostate cancer models.
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PMID:Vitamin D receptor: a potential target for intervention. 1223 Oct 68

Vitamin D plays a pivotal role in the pathogenesis and treatment of renal bone disease. Vitamin D levels decline in the early phase of renal failure, however, through a compensatory mechanism parathyroid hormone (PTH) stimulates the production of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol) to return it to normal circulating concentrations. Nevertheless, resistance to calcitriol is observed and may be related to the decreased presence of the heterodimeric, DNA-binding partner for the vitamin D receptor protein. In end-stage kidney disease (ESKD) the circulating levels of calcitriol are invariably low. The indications of vitamin D therapy are the replacement of the missing hormone vs suppression of hyperparathyroidism (HPT) requiring daily low-dose oral vs intermittent 'pulse' or oral administration. However, this therapy must be accompanied by careful patient monitoring to avoid hypercalcaemia and low bone turnover. Low bone turnover is not merely a histologic entity, but a clinical condition associated with a high risk of extraosseous calcifications, in particular in the cardiovascular system, leading to increased morbidity. Thus, determination of bone turnover in patients with ESKD is essential. Bone biopsy is the gold standard to assess bone turnover, however, it is not always available and nephrologists rely on PTH levels. The intact PTH assay measures PTH(1-84) and large C-PTH fragments, which may antagonize the PTH(1-84) effects on bone. An assay that measures exclusively PTH(1-84) has recently become available and a calculated PTH(1-84)/C-PTH fragment ratio has been shown to be the best predictor of bone turnover in patients with ESKD not treated with vitamin D or with other medications known to affect bone metabolism. 1,25-dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) is a vitamin D analogue that could control serum PTH concentrations without deleterious effects on bone.
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PMID:Use and indication of vitamin D and vitamin D analogues in patients with renal bone disease. 1238 63

The active form of vitamin D3 can regulate epidermal keratinization by inducing terminal differentiation; and mice lacking the vitamin D receptor display defects leading to postnatal alopecia. These observations implicate the vitamin D3 pathway in regulation of hair growth. We tested the ability of 1,25 dihydroxyvitamin D3 and its synthetic analogs to stimulate hair growth in biege/nude/xid (BNX) nu/nu (nude) mice exhibiting congenital alopecia. Nude mice were treated with different vitamin D3 analogs at doses that we had previously found to be the highest dose without inducing toxicity (hypercalcemia). The mice were monitored for hair growth and were scored according to a defined scale. Skin samples were taken for histological observation of hair follicles and for extraction of RNA and protein. Vitamin D3 analogs dramatically stimulated the hair growth of nude mice, although parental 1,25 dihydroxyvitamin D3 had no effect. Hair growth occurred in a cyclical pattern, accompanied by formation of normal hair follicles and increased expression of certain keratins (Ha7, Ha8, and Hb3). Vitamin D3 analogs seem to act on keratinocytes to initiate hair follicle cycling and stimulate hair growth in mice that otherwise do not grow hair.
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PMID:Vitamin D3 analogs stimulate hair growth in nude mice. 1239 36


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