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)

Parathyroid hormone-related protein (PTHrP) plays an important role in the pathogenesis of malignant hypercalcemia by stimulating bone resorption and/or renal tubular reabsorption of calcium. In cultured cancer cells, its production can be influenced by various factors or ions, but the regulation of its production is still poorly understood. We investigated the effects of stimulators of cAMP synthesis on PTHrP release by a human lung squamous-carcinoma cell line (BEN). In superfused cells grown on microcarrier beads, PTHrP production was significantly increased after incubation with calcitonin for only 20 min. The release of immunoreactive and bioactive PTHrP was increased by incubating the cells with forskolin, 3-isobutyl-1-methylxanthine or dibutyryl cAMP even in the presence of the protein-synthesis inhibitor cycloheximide for 6 hr. The calcitonin-mediated stimulation was not accompanied by concomitant changes in PTHrP mRNA. The microfilament-disrupter cytochalasin D was shown to enhance the basal and calcitonin-induced production of PTHrP. These results indicate that stimulators of cAMP synthesis enhanced PTHrP release by BEN cells.
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PMID:Cyclic AMP increases the release of parathyroid hormone-related protein from a lung-cancer cell line. 750 94

We compared the effects of parathyroid hormone (PTH1-34) and parathyroid hormone-related protein (PTHrp1-34) on osteocalcin release in the isolated rat hindlimb and in intact and thyroparathyroidectomized (TPTX) rats. PTH1-34 suppressed osteocalcin release from perfused rat hindquarters, while PTHrp1-34 had no effect on osteocalcin release, despite comparable stimulation of cAMP production. Similarly, serum osteocalcin declined in the intact and TPTX animals by 5 h after a single dose of PTH1-34, while there was no response to PTHrp1-34. Chronic administration of PTH1-34 or PTHrp1-34 produced comparable hypercalcemia and hypophosphatemia in sham-operated and TPTX animals. Chronic PTH1-34 administration produced significant increases in serum osteocalcin both in the sham-operated rats and in the TPTX animals. However, in animals chronically treated with PTHrp1-34, there was no change at any time point in osteocalcin in either sham-operated or TPTX rats. These differences could be inherent or merely due to potency differences between the two peptides.
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PMID:A comparison of the effects of parathyroid hormone and parathyroid hormone-related protein on osteocalcin in the rat. 757 14

Parathyroid hormone-related protein (PTHrP) is the factor responsible for the syndrome of humoral hypercalcemia of malignancy (HHM). The syndrome is well documented in adult cancer patients, but has not previously been described in young children. We report the case of a 3-month-old infant who developed refractory hypercalcemia (peak total calcium 13.8 mg/dl; normal 8.5-10.5, ionized calcium 3.3 meq/l; normal 2.0-2.5) associated with a high-grade, poorly differentiated malignant hepatic sarcoma. Parathyroid hormone (intact) levels were suppressed (7.5 pg/ml; normal 10-65). Fractional excretion of phosphate was markedly elevated (73.5%; normal 8%-20%) as were urinary cAMP levels (12.48 nmol/dl glomerular filtrate; normal 1.83-4.47) suggesting a PTH-like effect. Increased levels of PTHrP were present both in the serum (4.9 pmol/l; normal for adults < 1.5) and ascitic fluid (6.1 pmol/l). Since previous studies have demonstrated a potential role for PTHrP in the regulation of embryonal tissue differentiation and transmembrane calcium flux, our observation of elevated PTHrP levels associated with the development of a poorly differentiated hepatic sarcoma in a young infant may provide insight into the molecular mechanisms underlying HHM. We suggest that serum or plasma PTHrP levels be determined in all children with hypercalcemia of malignancy in whom the hypercalcemia cannot otherwise be explained.
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PMID:Fatal parathyroid hormone-related protein-induced humoral hypercalcemia of malignancy in a 3-month-old infant. 781 27

Parathyroid hormone (PTH) and PTH-related peptide (PTH-rP) bind to a common receptor and initiate second-messenger cascades that stimulate bone turnover and hypercalcemia. However, PTH is more potent than PTH-rP in inducing bone resorption and coupled bone metabolism in intact tissue, suggesting that these proteins elicit dissimilar postreceptor responses. We compared the effects of PTH and PTH-rP on osteoblastic retraction, an early event that must occur before the osteoclast can achieve access to the underlying bone mineral and begin resorption. MC3T3-E1 mouse osteoblasts were incubated in vehicle or 4.8 nM PTH or PTH-rP with or without 1 mM dibutyryl cAMP (Bt2cAMP). Morphologic changes were observed from 0 to 120 min. PTH caused marked retraction within minutes, which was not enhanced by Bt2cAMP. PTH-rP or Bt2cAMP induced slower, more modest retraction than PTH. The combined effect of PTH-rP plus Bt2cAMP was greater than that of PTH-rP, but less than that of PTH. PTH-rP and PTH had similar effects on cAMP generation. Thus, compared to PTH, PTH-rP induces less osteoblastic retractile response, exposing less bone surface to osteoclastic resorption. This may account for its lower hypercalcemic potency in vivo and contribute to its relative inability to stimulate coupled bone resorption and formation.
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PMID:PTH and PTH-rP elicit dissimilar retractile responses in murine MC3T3-E1 osteoblasts. 798 66

Plasma parathyroid hormone related-protein (PTHrP) may inhibit the calcium-lowering effect of bisphosphonate therapy. In this prospective study we examined the relationship between plasma PTHrP levels, renal tubular markers of calcium reabsorption, and the effectiveness of intravenous bisphosphonate therapy (IVBPT) in lowering serum calcium in patients with hypercalcaemia of malignancy (HM), with and without bone metastases. Thirty-five symptomatic hypercalcaemic patients (17 without and 18 with bone metastases) were treated with IVBPT (pamidronate 30-60 mg or BM21.0955 2-6 mg). Normocalcaemia was achieved in 24/35 (71%) patients with a mean fall in serum calcium of 0.85 mmol l-1 (range 0.11-1.93, P < 0.001). In the 35 patients studied, serum calcium levels reached a nadir between days 3 and 7, and this was accompanied by a small but significant reduction in plasma PTHrP levels (median reduction 0.77 pmol l-1, P = 0.007). Patients who responded to bisphosphonate therapy by becoming normocalcaemic had significantly lower basal plasma PTHrP levels, mean 4.06 vs 8.2 pmol l-1 (P < 0.04). A significant reduction in urinary calcium excretion was seen (mean 106 mumol l-1, P < 0.02) in patients with bone metastases, and urinary cAMP (mean 170 mmol l-1, P < 0.01) fell in all patients. Patients without demonstrable bone metastases had significantly higher plasma PTHrP levels (P < 0.002), required more doses of IVBPT, and had a poorer reduction in serum calcium compared with patients with bone metastases, only one of whom required more than one dose. We conclude that circulating PTHrP has an important role in increasing renal tubular reabsorption of calcium in HM, thus reducing the effectiveness of bisphosphonate therapy, particularly in patients with humoral HM and no bone metastases.
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PMID:Response to intravenous bisphosphonate therapy in hypercalcaemic patients with and without bone metastases: the role of parathyroid hormone-related protein. 801 31

A 78-year old male with ureteral carcinoma manifesting hypercalcemia is reported. He was diagnosed as having ureteral carcinoma of the left side 2 years previously and was treated by nephrectomy with ureterovesicostomy. In October 1991, he was admitted for anorexia. A clinical examination revealed recurrence of the ureteral carcinoma with metastasis to the rectum and liver. His serum calcium level was elevated (13.9 mg/dl). In addition to rehydration and furosemide, treatment with eel-calcitonin and prednisolone failed to decrease his serum calcium level. Finally, he was administered mithramycin but he died 13 days later. He had no evidence of bone metastasis or hyperparathyroidism. Nephrogenic cAMP and urinary parathyroid hormone-related protein (PTHrP) were markedly elevated. Immunohistochemical study demonstrated expression of PTHrP in the tumor cells. Thus, the hypercalcemia was thought to be mediated by PTHrP secreted from the neoplastic tumor. Although there have been several reports of ureteral carcinoma associated with humoral hypercalcemia of malignancy, this is considered to be the first case associated with elevation of PTHrP.
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PMID:Humoral hypercalcemia of malignancy associated with parathyroid hormone-related protein producing transitional cell carcinoma of the ureter. 801 40

Although hypercalcemia is a serious and frequent complication of lung cancer, it is not commonly investigated in our country. We studied the prevalence of hypercalcemia in 90 random lung cancer patients from the Department of Pneumology, Escola Paulista de Medicina. The following histological types were found: 35 Squamous cells carcinomas (CEC), 30 Adenocarcinomas (AdenoCa), 11 Small cells carcinomas (CIPC), 2 Large cells carcinomas (TGC), 1 Carcinoid, 1 Mesothelioma, 2 Undifferentiated carcinomas, 1 Adenosquamous, 1 in situ carcinoma and 4 metastatic tumors. Ionized Ca (Ca-i) was measured in blood samples of all patients. Hyperparathyroidism was excluded by PTH and cAMP determinations in the hypercalcemic patients (Ca-i > 1.29 mmol/L). We found elevated levels of Ca-i (range = 1.30 to 2.0 mmol/L) in 18 patients (20%), being: 12 CEC (66.7%), 3 AdenoCa (16.7%), 2 CIPC (11.1%) and 1 TGC (5.6%). The PTH levels were low or suppressed in all 18 patients, but cAMP determinations were elevated in 6 out of 12 patients. Hypercalcemia is then a very frequent complication of lung cancer (20%), and PTH measurement was able to exclude a hyperparathyroidism in all cases studied.
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PMID:[Prevalence of hypercalcemia in patients with lung cancer]. 824 7

Recombinant human interleukin-1 (rhIL-1) can induce an elevation in calcium that has been ascribed exclusively to the stimulation of bone resorption. In the present study, we investigated whether rhIL-1 could also enhance the renal tubular reabsorption of calcium. The chronic influence of recombinant human rhIL-1 on renal calcium transport was investigated in thyroparathyroidectomized rats. Administration of rhIL-1 at the dose of 1.5 micrograms/day sc for 6 days induced a significant elevation in plasma calcium that was associated with a slight but significant decrease in the urinary excretion of calcium. Recording of the urinary calcium excretion expressed per ml glomerular filtrate at various plasma calcium levels, as achieved by acutely infusing calcium gluconate, indicates that rhIL-1 enhanced the tubular reabsorption of calcium. The calculated index of the tubular reabsorption of calcium (TRCal) was significantly increased by rhIL-1 (2.18 +/- 0.14 versus 1.79 +/- 0.07 mmol/l GFR, p < 0.05, in vehicle-treated rats). The change in the renal handling of calcium was not associated with stimulation of the tubular reabsorption of magnesium. Acute administration of a large dose (24 micrograms given in a bolus IV injection) of rhIL-1 enhanced within minutes the urinary excretion of prostaglandin E2. This effect was followed by a significant increase in urinary cAMP excretion and associated with a lower urinary calcium excretion. In conclusion, the results presented in this study indicate that rhIL-1 administered chronically selectively stimulated the tubular reabsorption of calcium. Experimental evidence suggests that this effect is mediated by prostaglandin-induced cAMP generation. These data strongly suggest that changes in the tubular handling of calcium could contribute to rhIL-1-induced hypercalcemia.
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PMID:Stimulation by interleukin-1 of renal calcium reabsorption in thyroparathyroidectomized rats. 825 59

Parathyroid hormone-related protein is responsible for the hypercalcaemia caused by many tumours. Measurement of parathyroid hormone-related protein is becoming more accessible with the introduction of commercial assays. We report a case of hypercalcaemia of malignancy secondary to parathyroid hormone-related protein in a woman with renal carcinoma. The parathyroid hormone-related protein was assayed using a new immunoradiometric assay. We demonstrated an initial fall in parathyroid hormone-related protein and calcium levels after surgery and a rise in both before clinical relapse. However, the clinical relapse was itself associated with a fall in serum parathyroid hormone-related protein, nephrogenous cAMP and calcium, suggesting that the tumour had stopped producing parathyroid hormone-related protein or perhaps that post-translational processing had occurred as the tumour advanced. The tumour was investigated for parathyroid hormone-related protein mRNA content using reverse transcriptase polymerase chain reaction, both at diagnosis in surgically removed material, and using post-mortem specimens. The level of parathyroid hormone-related protein mRNA, while present, was much reduced in the recurrent tumour suggesting that active parathyroid hormone-related protein production fell substantially as the tumour advanced. This case suggests that, although demonstration of parathyroid hormone-related protein in hypercalcaemia is useful for diagnosis, tumoral secretion of this product may alter.
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PMID:Hypercalcaemia due to parathyroid hormone-related protein: long-term circulating levels may not reflect tumour activity. 828 89

A two-site immunoradiometric assay (IRMA) of parathyroid hormone-related protein (PTHrP) was employed to react with circulating concentrations of PTHrP in 14 patients with hepatocellular carcinoma (HCC) and hypercalcemia (> 10.6 mg/dl). Eleven of them had unresectable lesions and three received transcatheter arterial chemo-embolization (TACE) treatment. Patients had no evidence of bony metastases and only one had evidence of a parathyroid lesion (by bone scan and serum parathyroid hormone level, respectively). The urinary cAMP level was increased in all patients, but the serum 1,25-dihydroxyvitamin D and plasma cAMP levels varied. Twelve patients had elevated alpha-fetoprotein (AFP) (> 400 ng/ml) and two of them had mildly elevated AFP levels (11 and 147 ng/ml). Their PTHrP concentrations were elevated (7.1 to 33.2 pmol/l), compared with normal levels obtained in our laboratory (< 3.5 pmol/l). A significant decrease in plasma PTHrP (from 27.4 to 5.2 pmol/l), serum calcium concentrations (from 16.3 to 9.4 mg/dl) and AFP levels (from 64,787 to 3129 ng/ml) was observed on the day following TACE treatment. These results, by using an improved technique, extend the findings that hypercalcemia in patients with HCC is associated with increased renal reabsorption of calcium and increased bone resorption of PTHrP generated by HCC.
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PMID:Hypercalcemia and parathyroid hormone-related protein in hepatocellular carcinoma. 829 94


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