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)

1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1alpha,25(OH)(2)D(3) can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized (3)H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1alpha,25(OH)(2)D(3) analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2alpha- or 2beta-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1alpha,25(OH)(2)D(3). The (3)H-thymidine incorporation data were supported by the cell counting data after cells were treated with 1alpha,25(OH)(2)D(3), 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) or 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) for 7 days. 19-Nor-2alpha-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) and 19-nor-2beta-(3-hydroxypropyl)-1alpha,25(OH)(2)D(3) were also shown to be about 10-fold more active than 1alpha,25(OH)(2)D(3) in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1alpha,25(OH)(2)D(3) molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Evaluation of C-2-substituted 19-nor-1alpha,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer. 1720 93

Phosphate homeostasis is preserved during variations in phosphate intake by short-term intrinsic renal and intestinal adaptations in transport processes, and by more long-term hormonal mechanisms, which regulate the efficiency of phosphate transport in the kidney and intestine. Recently, several phosphaturic peptides such as fibroblast growth factor 23 (FGF-23), secreted frizzled-related protein-4 (sFRP-4), extracellular phosphoglycoprotein (MEPE) and fibroblast growth factor 7 (FGF-7) have been shown to play a pathogenic role in several hypophosphatemic disorders such as tumor-induced osteomalacia (TIO), autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), the McCune-Albright syndrome (MAS) and fibrous dysplasia (FD). These proteins induce phosphaturia and hypophosphatemia in vivo, and inhibit sodium-dependent renal phosphate transport in cultured renal epithelial cells. Interestingly, despite the induction of hypophosphatemia by FGF-23 and sFRP-4 in vivo, serum 1, 25-dihydroxyvitamin D (1alpha,25(OH)(2)D) concentrations are decreased or remain inappropriately normal, suggesting an inhibitory effect of these proteins on 25-hydroxyvitamin D 1alpha-hydroxylase activity. In FGF-23 knockout mice, 25-hydroxyvitamin D 1alpha-hydroxylase expression is increased and elevated serum 1alpha,25(OH)(2)D levels cause significant hypercalcemia and hyperphosphatemia. MEPE, however, increases circulating 1alpha,25(OH)(2)D. Circulating or local concentrations of these peptides/proteins may regulate 25-hydroxyvitamin D 1alpha-hydroxylase activity in renal tissues under physiologic circumstances.
J Steroid Biochem Mol Biol 2007 Mar
PMID:The phosphatonins and the regulation of phosphate transport and vitamin D metabolism. 1722 71

Secondary hyperparathyroidism (2 degrees HPT) commonly develops in patients with chronic kidney disease (CKD) in response to high phosphate, low calcium and low 1,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. High PTH levels increase the rate of bone turnover, with a net efflux of calcium and phosphate leading to vascular calcification and coronary artery disease. Treatment of 2 degrees HPT with 1alpha,25(OH)(2)D(3) and calcium-based phosphate binders often produces hypercalcemia and over-suppression of PTH, resulting in adynamic bone that cannot buffer excess calcium and phosphate, which increases the risk of vascular calcification. It is essential, then, to reduce PTH levels to a range that supports normal bone turnover and minimizes ectopic calcification. Vitamin D analogs that inhibit PTH gene transcription and parathyroid hyperplasia, and that have less calcemic activity than 1alpha,25(OH)(2)D(3,) have provided a greater safety margin for the treatment of 2 degrees HPT, as well as enhancing the survival of CKD patients. Although several analogs with less calcemic activity are now used in patients (paricalcitol and doxercalciferol in the USA, and OCT and falecalcitriol in Japan), efforts to develop even more selective analogs continue. Parathyroid glands express both 25-hydroxylase and 1alpha-hydroxylase and may be capable of activating prohormones or prodrugs to suppress PTH and parathyroid growth by an autocrine mechanism. Moreover, the introduction of non-calcium-based phosphate binders (sevelamer and lanthanum carbonate) and cinacalcet (an allosteric activator of the calcium receptor that reduces PTH and the serum calciumxphosphate product) may reduce the risk of hypercalcemia with vitamin D therapy. Combining these agents with higher doses of vitamin D compounds may achieve greater suppression of PTH and possibly enhance survival in patients with chronic kidney disease.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Vitamin D analogs for secondary hyperparathyroidism: what does the future hold? 1736 85

The active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is an endocrine hormone whose classic role is the maintenance of calcium homeostasis. It is well documented that 1,25(OH)(2)D(3) also has anti-tumor effects on a number of cancers and cancer cell lines including breast, colorectal, gastric, liver, ovarian, prostate, and non-melanoma skin cancers. Included in the anti-tumor activities of 1,25(OH)(2)D(3) are its ability to cause antiproliferation, prodifferentation and decrease angiogenesis. Furthermore, through regulation of the plaminogen activator (PA) system and a class of proteolytic enzymes called matrix metalloproteinases (MMPs), 1,25(OH)(2)D(3) reduces the invasive spread of tumor cells. Because of the calcemic limitations of using 1,25(OH)(2)D(3) as a therapy, we have tested the effects of a novel Gemini vitamin D analogue, Deuterated Gemini (DG), on mouse colorectal cancer. We demonstrated that DG is more potent in reducing tumor volume and mass, compared to control and 1,25(OH)(2)D(3). DG significantly prevented (100% reduction, p<0.05) the invasive spread of colorectal tumor cells into the surrounding muscle, and had no effect on serum calcium levels. Thus, DG acts as a selective vitamin D receptor modulator (SVDRM) by enhancing select anti-tumor characteristic 1,25(OH)(2)D(3) activities, without inducing hypercalcemia. Thus, DG shows promise in the development of colorectal cancer therapies.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Selective vitamin D receptor modulators and their effects on colorectal tumor growth. 1736 90

Calcitonin is a thirty-two amino acid peptide that contains an N-terminal disulphide bridge and a C-terminal prolineamide residue. It is released from thyroid parafollicular C-cells and its direct actions on the osteoclast account for its physiological effects whether as a hypocalcaemic agent and a potent inhibitor of bone resorption. These effects likely reflect actions upon a number of specific osteoclast cell surface receptors that initiate intracellular signaling events through both cyclic AMP and calcium mediated second messenger pathways. Studies of its potent anti-resorptive effects have significant translational implications in the management of Paget's bone disease, osteoporosis, and hypercalcaemia. This chapter summarizes major concepts in the synthesis and structure of calcitonin and then proceeds to outline its cellular, molecular actions and therapeutic applications, whilst seeking to provide a reference source. More detailed accounts have been given on different aspects of calcitonin physiology and biochemistry in a number of recent reviews by ourselves and others (155,157, Zaidi et al., 1994; 2002).
Cell Mol Biol (Noisy-le-grand) 2006 Sep 29
PMID:Molecular physiology and pharmacology of calcitonin. 1753 52

The presence of vascular calcification (VC) is a predictor of poor survival in the general population. The development of VC is an active process that requires a pre-existing injury as an inducer and promoting factors such as hyperphosphatemia and hypercalcemia, as well as a deficiency in calcification repressor factors. Vascular smooth muscle cells possess an endogenous enzyme system for the biosynthesis of the vitamin D hormone calcitriol from its precursor 25-hydroxyvitamin D and also a cytosolic calcitriol receptor, indicating that the vasculature is an important target tissue for vitamin D. The toxic effects of supra-physiological vitamin D dosages on the vasculature have been known for several decades. Recent experimental data also demonstrate important physiological effects of vitamin D on factors that are protective for vascular health. This review article summarises the molecular basis of protective and toxic vitamin D actions on the vasculature. Chronic kidney disease can be considered as a human model of severe VC and poor survival. The disease is associated with calcitriol deficiency, hyperparathyroidism, and hyperphosphatemia. Evidence is increasing that phosphate overload plays a key role in the process of VC in chronic kidney disease. The first clinical studies indicate that vitamin D receptor activation can improve survival in these patients. Although less severe than in chronic kidney disease, vitamin D deficiency and secondary hyperparathyroidism are also frequent in the general population, especially in elderly and obese subjects. Future studies should focus on the impact of vitamin D deficiency on VC and clinical outcome in these groups.
Mol Aspects Med 2008 Dec
PMID:Protective and toxic effects of vitamin D on vascular calcification: clinical implications. 1853 38

The vitamin D endocrine system plays a central role in mineral ion homeostasis through the actions of the vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], on the intestine, bone, parathyroid gland, and kidney. The main function of 1,25(OH)(2)D(3) is to promote the dietary absorption of calcium and phosphate, but effects on bone, kidney and the parathyroids fine-tune the mineral levels. In addition to these classical actions, 1,25(OH)(2)D(3) exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. These biological activities of 1,25(OH)(2)D(3) have suggested a multitude of potential therapeutic applications of the vitamin D hormone for the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). Unfortunately, the effective therapeutic doses required to treat these disorders can produce substantial hypercalcemia. This limitation of 1,25(OH)(2)D(3) therapy has spurred the development of vitamin D analogs that retain the therapeutically important properties of 1,25(OH)(2)D(3), but with reduced calcemic activity. Analogs with improved therapeutic indices are now available for treatment of psoriasis and secondary hyperparathyroidism in chronic kidney disease, and research on newer analogs for these indications continues. Other analogs are under development and in clinical trials for treatment of various types of cancer, autoimmune disorders, and many other diseases. Although many new analogs show tremendous promise in cell-based models, this article will limit it focus on the development of analogs currently in use and those that have demonstrated efficacy in animal models or in clinical trials.
Mol Aspects Med 2008 Dec
PMID:Vitamin D analogs: therapeutic applications and mechanisms for selectivity. 1855 10

The calcium-sensing receptor (CASR), a plasma membrane G-protein-coupled receptor, is expressed in parathyroid gland and kidney, and controls systemic calcium homeostasis. Inactivating CASR mutations are associated with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism, and activating mutations cause autosomal dominant hypocalcemia (ADH). CASR mutation identification plays an important role in the clinical management of mineral metabolism disorders. We describe here a high-throughput method using screening with denaturing high performance liquid chromatography (DHPLC) to initially interrogate 12 amplicons covering translated exons and exon/intron boundaries, followed by sequencing of any amplicon with a modified melting curve relative to wild type, and direct sequencing of a 13th amplicon encoding the COOH-terminal tail to distinguish causative mutations from three common missense single nucleotide polymorphisms. A blinded analysis of 32 positive controls representing mutations throughout the CASR sequence, as well as 22 negative controls, yielded a concordance rate of 100%. We report eight novel and five recurrent FHH mutations, along with six novel and two recurrent ADH mutations. Thus, DHPLC provides a rapid and effective means to screen for CASR mutations.
J Mol Endocrinol 2009 Apr
PMID:Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. 1917 54

Calciphylaxis is a poorly understood syndrome of vascular calcification and skin necrosis. It affects 1-4% of the population with end stage renal disease (ESRD). Disorders implicated in the pathogenesis of calciphylaxis include chronic renal failure, hypercalcemia, hyperphosphatemia, an elevated calcium-phosphate product, and secondary hyperparathyroidism (Essary, L.R. and Wick, M.R. (2000) Cutaneous calciphylaxis. An underrecognized clinicopathologic entity. Am. J. Clin. Pathol. 113, 280-287, Beitz, J.M. (2004) Calciphylaxis:an uncommon but potentially deadly form of skin necrosis. Am. J. Nurs. 104, 36-37.). Although these abnormalities are extremely common in-patients with ESRD, calciphylaxis is relatively rare. The mortality rate of calciphylaxis is about 60-80%. The leading cause of death is sepsis from necrotic skin lesions (Hitti,W.A., Papadimitriou, J.C., Bartlett, S. and Wali, R.K. (2007) Spontaneous cutaneous ulcers in a patient with a moderate degree of chronic kidney disease: a different spectrum of calciphylaxis. Scand. J. Urol. Nephrol.1-3.). Here, we report a case of calciphylaxis in a 23-year-old female with past history of chronic renal failure, renal transplantation and intake of immunosuppressive drug. The relevant literature was discussed.
Exp Mol Pathol 2009 Apr
PMID:Calciphylaxis cutis: a case report and review of literature. 1934 63

The calcium sensing receptor (CaSR) is a Family C/3 G protein-coupled receptor that translates changes in extracellular Ca(2+) into diverse intracellular signals. Loss-of-function mutations in human CaSR cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. CaSR must navigate a number of endoplasmic reticulum quality control checkpoints during biosynthesis, including a conformational/functional checkpoint. Here we examine the biosynthesis of 25 CaSR mutations causing familial hypocalciuric hypercalcemia /neonatal severe hyperparathyroidism using immunoprecipitation, biotinylation, and functional assays. We define classes of CaSR mutants based on their biosynthetic profile. Class I CaSR mutants are not rescued to the plasma membrane. To dissect the organellar compartments that class I mutants can access, we engineered a cleavage site for the proprotein convertase furin into the extracellular domain of wild-type CaSR and class I mutants. Based on absence or presence of cleavage fragments, we find most mutants are degraded from the endoplasmic reticulum (no furin-mediated cleavage), whereas others access the Golgi (furin-mediated cleavage) before degradation. Class II CaSR mutants show increased expression and/or enhanced plasma membrane localization upon treatment with MG132 or the pharmacochaperone NPS R-568, permitting assay of functional activity. Of the 10 CaSR mutants that exhibit plasma membrane localization, only two did not show enhanced functional activity after rescue with NPS R-568. The established approaches can be used with current and newly identified CaSR mutations to identify the location of biosynthetic block and to determine the likelihood of rescue by allosteric agonists.
Mol Endocrinol 2009 Jul
PMID:Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. 1938 9


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