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)

To investigate the mechanism of the inhibitory effects of interferon-gamma (IFN-gamma) on bone resorption, the effects of murine IFN-gamma on 45Ca release from prelabeled fetal mouse forearm bones were investigated. Murine IFN-gamma usually did not affect basal 45Ca release but almost completely and equipotently inhibited bone resorption induced by PTH(1-34), PTH-rP(1-34), 1,25(OH)2D3, and interleukin 1 (IL-1). The half-maximal concentration for inhibition of bone resorption induced by IL-1 alpha was 25.8 +/- 14.6 U/ml (mean +/- SD for 13 experiments), which is not different from those for PTH, PTH-rP, and 1,25(OH)2D3. There was no correlation between prostaglandin E2 concentration in the conditioned medium and 45Ca release from the IFN-gamma-treated forearm bones. The inhibitory effect of IFN-gamma on bone resorption induced by PTH-rP (1-34) or IL-1 alpha continued during 6 days of culture, whereas that of calcitonin disappeared after 2 days of culture. These findings suggest that IFN-gamma non-preferentially inhibits bone resorption induced by various bone-resorbing factors in fetal mouse forearm bones via a PGE2-independent mechanism. As no escape phenomenon developed in IFN-gamma-treated bones, the cytokine may be potentially useful for treatment of certain patients with malignancy-associated hypercalcemia.
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PMID:Prolonged and ubiquitous inhibition by interferon gamma of bone resorption induced by parathyroid hormone-related protein, 1,25-dihydroxyvitamin D3, and interleukin 1 in fetal mouse forearm bones. 212 24

The structure of a novel protein, parathyroid hormone-related protein (PTHrP), secreted by human tumors associated with hypercalcemia has recently been determined. Administration of a synthetic fragment of this protein in vivo reproduces features of the clinical paraneoplastic syndrome of humoral hypercalcemia of malignancy and produces biologic responses closely similar to those obtained with parathyroid hormone (PTH). A PTH antagonist designed to reversibly occupy PTH receptors inhibited major actions of the tumor peptide in vivo, including phosphaturia, urinary cAMP excretion, and increased serum ionized calcium. These studies indicate that PTHrP and PTH mediate their bioactivities through shared receptors in vivo and establish a potential specific mechanism-based approach utilizing PTH antagonists for the therapy of tumor-associated hypercalcemia.
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PMID:The synthetic human parathyroid hormone-related protein is inhibited by a parathyroid hormone antagonist in rats in vivo. 216 20

The PTH-like peptide (PTHLP) responsible for hypercalcemia in many patients with humoral hypercalcemia of malignancy (HHM) acts on PTH receptors in bone and kidney, and large doses of PTHLPs have been shown to reduce urinary calcium excretion. However, PTHLPs have not been assessed quantitatively for effects on renal calcium excretion at concentrations (5-100 pM) now known to be found in the serum of patients with HHM. We perfused isolated rat kidneys with synthetic [tyr-36] PTHLP-(1-36)amide [PTHLP-(1-36)], PTHLP-(1-74), and synthetic bovine PTH-(1-34). The ratio of calcium to sodium clearances (CCa/CNa), a measure of distal tubular calcium transport, was reduced to the same extent by PTH, PTHLP-(1-36), and PTHLP-(1-74) (54.3 +/- 3.9, 52.9 +/- 3.9, and 52.7 +/- 1.3% reductions from control), respectively) at maximal doses (35-50 pM and higher), with half-maximal effects at 10, 18, and 32 pM, respectively. PTH, PTHLP-(1-36), and PTHLP-(1-74) all increased fractional phosphate excretion over control (p less than 0.05 each). All three peptides were natriuretic, at least doubling fractional Na excretion (p less than 0.05 or less). Urinary cAMP excretion was increased by all three. None had any effect on GFR or renal vascular resistance. These results indicate that clinically relevant concentrations of PTHLPs are anticalciuretic and natriuretic, with maximal effects similar to those of PTH. Differences in anticalciuretic potencies are small but may explain differences among patients, depending on the size(s) and concentrations of the native circulating form(s) of the peptide.
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PMID:Quantitative evaluation of anticalciuretic effects of synthetic parathyroid hormonelike peptides. 216 24

The decrease in plasma Pi concentration and in Pi tubular reabsorption that is often encountered in malignant hypercalcemia may be ascribed to a tumor-produced parathyroid hormone (PTH)-related protein. However, tumors are known to synthesize a variety of substances, among which is transforming growth factor-alpha (TGF-alpha). We investigated the effects of TGF-alpha on Na-dependent Pi transport and on the response to PTH-related protein in cultured opossum renal epithelial cells. TGF-alpha caused a concentration- and time-dependent decrease in Na-dependent Pi transport. The inhibition of Na-dependent Pi transport was detectable by 14 h of incubation and maximal by 24 h. At that time, a concentration of 10 ng/ml of TGF-alpha produced a 35 +/- 1% inhibition. This was not associated with any change in prostaglandin production. The adenosine 3',5'-cyclic monophosphate (cAMP) response to PTH-related protein, PTH, prostaglandin E2 or forskolin, but not to pertussis toxin, was diminished in cells treated with TGF-alpha for 24 h. Similar effects on Na-dependent Pi transport and cAMP production were observed in cells incubated with epidermal growth factor. The inhibition of Na-dependent Pi transport induced by either PTH-related protein or PTH was reduced after incubation with TGF-alpha. Thus two different tumoral products, TGF-alpha and PTH-related protein, are each capable of inhibiting Na-dependent Pi transport in cultured renal cells. Both peptides may also interact and influence the effects of each other on renal Pi transport.
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PMID:Effect of transforming growth factor-alpha and parathyroid hormone-related protein on phosphate transport in renal cells. 217 62

During the past decade, specific mediators of bone destruction in hypercalcemia of malignancy have been identified and characterized. These humoral factors include parathyroid hormone-related protein, transforming growth factor alpha, and cytokines such as interleukin-1 and tumor necrosis factor. In metastatic hypercalcemia associated with breast cancer, prostaglandin secretion by tumor cells may be one of the important factors. Among the osteoclast activating factors associated with hypercalcemia in patients with myeloma, lymphotoxin plays a central but probably not exclusive role. Alterations of renal function in hematologic hypercalcemia may potentiate bone destruction that usually occurs in the presence of impaired rates of glomerular filtration. Further research is required to determine the relative contributions of bone and kidney to the pathogenesis of hypercalcemia of malignancy.
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PMID:Pathophysiology of cancer-associated hypercalcemia. 218 48

Parathyroid hormone-related protein (PTHrP) is invoked as the cause of humoral hypercalcaemia of malignancy (HHM); it is contained in the keratinocyte layer of normal skin; and there is evidence that is is produced by fetal parathyroids. Antibodies against synthetic PTHrP peptides have been raised in rabbits and sheep. This immunohistochemical study has found that primary parathyroid adenomata and hyperplastic glands from patients with chronic renal failure stain positively with antisera against PTHrP(1-34) and PTHrP(50-69). Primary hyperplastic glands are negative. No staining with anti-PTHrP(106-141) antiserum could be detected immunohistochemically in any of the parathyroid adenomata or hyperplasia.
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PMID:Immunohistochemical localization of parathyroid hormone-related protein in parathyroid adenoma and hyperplasia. 219 48

The isolated perfused rat kidney was used to study the effects of amino-terminal fragments of human parathyroid hormone, hPTH(1-34), bovine parathyroid hormone, bPTH(1-84) and of PTH-related proteins, PTHrP(1-34), PTHrP(1-84), PTHrP(1-108) and PTHrP(1-141) on urinary bicarbonate excretion. PTHrP(1-34) (7 nmol/l), bPTH(1-84) (5.5 nmol/l) and hPTH(1-34) (7 nmol/l) had similar effects in increasing bicarbonate excretion with respect to the control. At lower concentrations (0.7 nmol/l) all PTHrP components, but not hPTH(1-34) or bPTH(1-84) increased bicarbonate excretion significantly. Infusions of PTHrP(1-108) and PTHrP(1-141) at 0.7 nmol/l, while associated with a rise in urinary bicarbonate concentration and excretion during the early stages of perfusion, produced a sharp decline in bicarbonate concentration and excretion in the latter part of perfusion. The different peptides produced no significant differences in glomerular filtration rate, fractional excretion of sodium or urine volume. The absence of substantial differences between the effects of hPTH(1-34) and PTHrP(1-34) are as noted in previous studies. The differences between PTHrP(1-108)/PTHrP(1-141) and PTHrP(1-34) demonstrated here are consistent with (1) the clinical manifestations of acidosis in hyperparathyroidism and alkalosis in humoral hypercalcaemia of malignancy, and (2) an independent action of a component of PTHrP beyond amino acids 1-34.
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PMID:Comparison of the effects of parathyroid hormone (PTH) and recombinant PTH-related protein on bicarbonate excretion by the isolated perfused rat kidney. 221 31

Discussed is the case of a 50-year-old man with a well advanced esophageal carcinoma who, during his final clinical course, suddenly developed hypercalcemia (max: 15.0 mg/ml). His serum parathyroid hormone level, however, remained within normal limits. On autopsy, an extensive metastasis to many organs and lymph nodes was noted but no evidence of a bone metastasis. Nude mice bearing the same tumoral tissue were found, on autopsy, to have similarly developed hypercalcemia and cells that were cultured were found to produce an excessive amount of Prostaglandin E2 (PGE2). These findings suggest that this humoral hypercalcemia of malignancy (HHM) was caused by excessive PGE2 produced by the tumor cells, although other possible factors should be investigated.
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PMID:[Esophageal carcinoma with hypercalcemia that appeared to be caused by prostaglandin E2 produced by the tumor cells]. 225 Mar 67

The mechanisms of paraneoplastic hypercalcemic syndromes are heterogeneous. Neoplastic hypercalcemia without bone metastatic disease is caused by parathyroid hormone related protein, whose action is comparable to parathyroid hormone. Growth transforming factors, platelet derived growth factor, tumor necrosis factors and interleukin 1 are also involved in humoral hypercalcemia of malignancy. In addition to these substances, hypercalcemia in bone metastatic disease may be related to PGE. Tumor necrosis factors and interleukin 1 play a major role in multiple myeloma as well as in Adult T cell Leukemia/Lymphoma where overproduction of vit D3 by lymphomatous cells can also be significant.
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PMID:[Hypercalcemia and neoplasms: recent advances in pathogenesis]. 229 Oct 7

The pathogenesis of hypercalcemia in malignancy has been enigmatic until recent years. Since the realization in 1980 that bioassays for parathyroid hormone detected a cross-reacting substance in malignancy, progress has been remarkably rapid. A parathyroid hormone-related protein was purified and identified by molecular cloning as a 141-amino acid peptide with limited homology to parathyroid hormone itself. Nonetheless, both peptides activate the parathyroid hormone receptor to produce hypercalcemia. It is now clear that the parathyroid hormone-related protein is the cause of hypercalcemia in most solid tumors, particularly squamous and renal carcinomas. New assays for the hormone as well as the related peptide have greatly simplified the differential diagnosis of hypercalcemia. At the same time, new agents for the treatment of hypercalcemia are becoming available, most notably the bisphosphonate drugs.
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PMID:Hypercalcemia in malignancy. 229 69


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