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)

Vitamin D derivatives have demonstrated anti-cancer activity, but their clinical use is precluded by hypercalcemia. Previously, we found that carnosic acid potentiates differentiation of human leukemia cells induced by low concentrations of 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)). In this study, we investigated if this effect is a general property of antioxidants, and whether there is a common mechanism whereby antioxidants potentiate monocytic differentiation. We found that all antioxidants tested enhanced differentiation-related cell cycle arrest induced by a low (1 nM) concentration of 1,25D(3). Addition of antioxidants to 1,25D(3) activated the JNK pathway as indicated by increased phosphorylation of c-jun and ATF-2, although each compound alone had a minimal effect. Antioxidants also enhanced the 1,25D(3)-induced AP-1 DNA binding and transactivation ability. Expression of Egr-1 and c-fos was increased by combinations of antioxidants and 1,25D(3), in parallel with the activation of the JNK pathway. The potentiation of differentiation by antioxidants was inhibited by JNK inhibitor SP600125 and a dominant negative JNK 1/2 construct, and Egr-1 and c-fos expression was proportionally decreased, suggesting that JNK pathway regulates these transcription factors. While potentiating the prodifferentiation effect of 1,25D(3), antioxidants did not promote the elevation of basal levels of intracellular calcium by 1,25D(3). The results indicate that JNK-AP1 pathway has an important role in the potentiation of 1,25D(3)-induced differentiation by antioxidants, and regulates expression of Egr-1 and c-fos. Combinations of antioxidants with 1,25D(3) should be further evaluated for use in cancer chemoprevention and therapy.
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PMID:Cooperation between antioxidants and 1,25-dihydroxyvitamin D3 in induction of leukemia HL60 cell differentiation through the JNK/AP-1/Egr-1 pathway. 1579 27

The renin-angiotensin system (RAS) plays a central role in the pathogenesis of hypertension. Recently, we discovered that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] functions as a negative endocrine regulator of renin biosynthesis, which provides a molecular basis to explore the potential of Vitamin D analogs as renin inhibitors to control the RAS. To search for renin-inhibiting Vitamin D analogs, we screened 20 Vitamin D analog compounds using As4.1-hVDR cell (a juxtaglomerular cell line) culture by Northern blot and luciferase reporter assays. We found that the Gemini compounds, which have two side-chains at carbon-20 position, were particularly active in suppressing renin expression. Eight Gemini compounds were identified that were equally or 10- to 100-times more potent than 1,25(OH)(2)D(3) in renin inhibition. These Gemini compounds also potently stimulate 25-hydroxyvitamin D 24-hydroxylase expression in As4.1-hVDR cells. Administration of compound RO-27-5646 [1,25-dihydroxy-21-(3-methyl-3-hydroxy-butyl)-19-nor-cholecalciferol] in mice caused a marked reduction in renal renin mRNA expression without invoking severe hypercalcemia as seen in 1,25(OH)(2)D(3) treatment. These data establish in principle that Vitamin D analogs can indeed inhibit renin expression in vitro and in vivo, and support the notion that low calcemic Vitamin D analogs can potentially be used as therapeutic agents to control the RAS.
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PMID:Analogs of 1alpha,25-dihydroxyvitamin D(3) as novel inhibitors of renin biosynthesis. 1587 26

Activated vitamin D continues to be the major treatment for suppressing parathyroid hormone (PTH) levels in dialysis patients who have secondary hyperparathyroidism. Active vitamin D compounds are distinguished by their ability to bind with high affinity to vitamin D receptors (VDRs) not only in the parathyroid glands, but in cells throughout the body. Because of recent data showing that pulsatile, intravenous vitamin D treatment (calcitriol or paricalcitol) confers a survival advantage in the dialysis population, there is new interest in understanding the systemic effects of VDR activation, particularly in the predialysis stages of chronic kidney disease (CKD), where high mortality rates from cardiovascular disease have recently been documented. Previous underutilization of calcitriol treatment to control PTH levels in stages 3 and 4 CKD was often due to concerns about its potential for accelerating the progression of CKD as a consequence of hypercalcemia, hypercalciuria, or hyperphosphatemia. Vitamin D analogs with selective VDR activity (such as paricalcitol) have great potential for preventing parathyroid hyperplasia and bone loss in early CKD without adversely affecting kidney function. Whether they also reduce cardiovascular morbidity and mortality in early CKD, as they appear to do in dialysis patients, remains to be determined.
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PMID:Vitamin D treatment in chronic kidney disease. 1607 55

We can define paraneoplastic syndromes as a combination of effects occurring far from the original location of the tumour and independently from the local repercussion of its metastases. Paraneoplastic hormonal syndromes depend on the secretion of hormonal peptides or their precursors, cytokines and, more rarely, thyroidal hormones and Vitamin D, which act in an endocrine, paracrine or autocrine way. Sometimes, paraneoplastic syndromes can be more serious than the consequences of the primary tumour itself and can precede, develop in parallel, or follow the manifestations of this tumour. It is important to recognise a paraneoplastic hormonal syndrome for several reasons, amongst which we would draw attention to three: 1) It can lead to the diagnosis of a previously undetected, underlying malign or benign neoplasia; 2) It can dominate the clinical picture and thus lead to errors with respect to the origin and type of primary tumour; and 3) It can follow the clinical course of the underlying tumour and thus be useful for monitoring its evolution. The molecular mechanisms responsible for the development of these syndromes are not well-known, but it is believed that they might be inherent to the mutations responsible for the primary tumour or depend on epigenetic factors such as methylation. In this review, we consider the following paraneoplastic hormonal syndromes: malign hypercalcaemia, hyponatraemia (inappropiate secretion of the antidiuretic hormone), ectopic Cushing's syndrome, ectopic acromegaly, hypoglycaemia due to tumours different from those of the islet cells and paraneoplastic gynaecomastia; we make a brief final reference to other hormones (calcitonin, somatostatin, and VIP).
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PMID:[Paraneoplastic hormonal syndromes]. 1615 18

Myelodysplastic syndrome (MDS) is often a pernicious disorder associated with pancytopenia in the elderly; therapeutic approaches need to balance their toxicities versus the symptoms of the disease. 1,25(OH)(2)-Vitamin-D(3) [1,25(OH)(2)D(3)] inhibits proliferation and induces differentiation of leukemic cells in vitro. Small clinical trials of 1,25(OH)(2)D(3) have shown modest efficacy in MDS; hypercalcemia prevented the administration of doses that have been shown to be effective in vitro. Paricalcitol [19-nor-1,25(OH)(2)D(2), Zemplar] has been approved by the FDA for treatment of secondary hyperparathyroidism. This Vitamin D analog is unique because it has little hypercalcemic potential; but in vitro, it has strong anti-leukemic activity. We conducted a clinical trial of oral paricalcitol to 12 MDS patients whose disease varied between an IPSS of low to high. Drug was well-tolerated in all patients. No responses were observed according to international working group (IWG) criteria. However, the platelet count of 1 of the 12 individuals rose from 53,500 to 120,000/microl blood over 5 weeks; but the patient succumbed to a fatal fungal infection. In summary, paricalcitol given as a single agent to MDS patients is therapeutically not very efficacious; further trials of the Vitamin D analog should be considered in combination with other approaches.
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PMID:Vitamin D(2) analog (Paricalcitol; Zemplar) for treatment of myelodysplastic syndrome. 1616 82

Currently, >300,000 patients with end-stage renal disease require dialysis. Secondary hyperparathyroidism is a serious complication of end-stage renal disease and can lead to renal osteodystrophy and other organ failure. Vitamin D sterols and phosphate binders are used to treat hyperparathyroidism, but they can cause hypercalcemia, which contributes to vascular and soft-tissue calcification. Cinacalcet (Sensipar) is the first agent in its class that treats secondary hyperparathyroidism by increasing the sensitivity of calcium sensing receptors. It is also indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. All clinical trials concluded that cinacalcet is effective for the reduction of parathyroid hormone, serum calcium, phosphorus, and calcium-phosphate product levels. Cinacalcet is available as a once-daily oral therapy. Adverse effects are generally mild.
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PMID:Cinacalcet hydrochloride (Sensipar). 1620 Jan 70

Vitamin D shows significant potential as a therapy for prostate cancer. However, its use in clinical trials has been hampered by its induction of hypercalcemia at serum concentrations required to suppress cancer cell proliferation. This has spurred the development of less calcemic analogs of vitamin D. In this article, we review the clinical trials and consider the future directions of the use of vitamin D and its analogs in the treatment or chemoprevention of prostate cancer. First, we summarize the epidemiological evidence leading to the hypothesis that vitamin D has anticancer activity. We then review the clinical trials using vitamin D analogs that involve patients with prostate cancer and conclude with a brief overview of our planned study with vitamin D5, [1alpha(OH)D5], which will begin shortly. Data for this review were identified by searches of PubMed, the Cochrane Library, Biosis, and references from relevant articles, using the search terms "vitamin D," "prostate cancer," "chemoprevention" and "vitamin D analog." Abstracts from recent international meetings were also reviewed but were only included when they were the only known reference to the clinical trial or the research mentioned. Only papers published in English were included.
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PMID:Clinical trials involving vitamin D analogs in prostate cancer. 1625 66

Vitamin D intoxication is a well-known cause of hypercalcemia in children. We report here the use of oral alendronate for the treatment of hypercalcemia due to vitamin D intoxication in a 7 month-old infant with nephrocalcinosis. The serum calcium levels were normalized without complications. Oral alendronate therapy may be safely used in hypercalcemia due to vitamin. D intoxication in pediatric patients with nephrocalcinosis resistant to hydration, diuretics or corticosteroids.
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PMID:Oral alendronate therapy for severe vitamin D intoxication of the infant with nephrocalcinosis. 1656 91

The conflicting results of previous evaluations of the influence of hypercalcemia on thyroid C-cells and the absence of reports on its influence on calcitonin (CT)-producing cells of the airways prompted this study. It aims to evaluate the activity and changing dynamics in CT-producing cells in rat thyroid glands and lungs after prolonged hypercalcemia. The hypercalcemia was induced by an intraperitoneal injection of 100,000IU of vitamin D(3) (Vigantol), Merck). Control and experimental rats were examined after 1, 7 and 14 days. Calcium and CT concentrations were measured in blood plasma. Paraffin wax embedded sections of thyroid and lungs were stained with hematoxylin and eosin. CT was detected immunohistochemically in thyroid C-cells and lung endocrine cells. Results showed increased calcium and CT concentrations in rat blood after vitamin D(3) administration, a statistically significant reduction in number of CT-positive cells in the thyroid with indications of their increased activity, and a statistically non-significant reduction of the number of cells immunopositive for CT in lungs after 1 day, and an increase after 7 days, compared to the control group. Lack of an obvious correlation in lung neuroendocrine cells among the rats with hypercalcemia may indicate the presence of other, perhaps local, functions for calcitonin.
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PMID:Comparative study of changes in activity of calcitonin-producing cells in the thyroid and lungs during hypercalcemia. 1676 3

Colorectal cancer is a disease that originates from the neoplastic transformation of epithelial cells of the colon and rectum, as a result of the accumulation of genetic and epigenetic aberrations. At least four sequential genetic changes, affecting one oncogene (KRAS) and three tumor suppressor genes (APC, SMAD4 and TP53), are required for the development of colorectal cancer. Abundant experimental studies and epidemiological data, as well as several human clinical trials suggest a protective effect of Vitamin D against colon carcinogenesis. Hypercalcemia, a side effect of natural Vitamin D, has currently restricted its therapeutic use; however, the development of new synthetic analogs with reduced hypercalcemic activity is promising for cancer therapy and prevention. Extensive research to elucidate the mechanisms underlying the anti-cancer action of Vitamin D is being undertaken. Understanding the complex molecular and cellular networks induced by Vitamin D or its analogs will improve the use of these compounds for the prevention and treatment of colorectal cancer.
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PMID:Colorectal cancer: potential therapeutic benefits of Vitamin D. 1715 47


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