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)

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome which is characterized by hypercalcemia resulting from secretion by tumors of a circulating bone-resorbing factor. Evidence suggests that in many instances this factor is an adenylate cyclase-stimulating protein which shares features with, but is distinct from, parathyroid hormone (PTH). The current report describes the purification to homogeneity from a humoral hypercalcemia of malignancy-associated tumor of a novel, basic, highly potent PTH-like adenylate cyclase-stimulating protein. This factor differs from previously described PTH-like factors with respect to size, amino acid composition, and specific activity.
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PMID:Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. 358 10

A variety of solid tumors secrete proteins that are immunochemically distinct from parathyroid hormone (PTH) but activate PTH-responsive adenylate cyclase. Such PTH-like proteins have been proposed as mediators of the hypercalcemia and hypophosphatemia frequently associated with malignancies. We purified to apparent homogeneity a PTH-like protein with a molecular weight of 6,000, that is produced by human renal carcinoma cells. The amino-terminal sequence of the PTH-like protein and that of human PTH were found to display at least five identities in the first 13 positions. The purified protein bound to PTH receptors, activated adenylate cyclase in renal plasma membranes, and stimulated cAMP formation in rat osteosarcoma cells. The PTH-like protein reproduced two additional effects of PTH, stimulation of bone resorption in fetal rat limb bone cultures and inhibition of phosphate uptake in cultured opossum kidney cells. These properties are consistent with a role for PTH-like proteins as mediators of the syndrome of malignancy-associated hypercalcemia.
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PMID:Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. 368 May 30

Peptides corresponding to the amino-terminal region of the parathyroid hormone-related protein (PTHrP) of humoral hypercalcemia of malignancy were synthesized. A 34-amino acid peptide, PTHrP(1-34), was two to four times more potent than bovine or human PTH(1-34) in bioassays promoting the formation of adenosine 3',5'-monophosphate (cAMP) and plasminogen activator activity in osteogenic sarcoma cells and adenylate cyclase activity in chick kidney membranes. Like parathyroid hormone itself, in which the activity resides in the first 34 residues, PTHrP peptides of less than 30 residues from the amino terminus showed substantially reduced activity. PTHrP(1-34) had only 6% of the potency of bovine PTH(1-34) in promoting bone resorption in vitro. PTHrP(1-34) strongly promoted the excretion of cAMP and phosphorus and reduced the excretion of calcium in the isolated, perfused rat kidney consistent with the symptoms seen in malignant hypercalcemia.
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PMID:Parathyroid hormone-related protein of malignancy: active synthetic fragments. 368 95

Three patients with hypercalcemia associated with malignant lymphoma and elevations in plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] are described. In addition to the elevation of circulating 1,25-(OH)2D, these three patients were characterized by suppressed immunoreactive PTH levels and urinary cAMP excretion, elevated fasting urinary excretion of calcium, and absence of adenylate cyclase-stimulating activity in the tumor extracts. Bone marrow biopsy and skeletal radionuclide scans were negative for lymphoma in two patients. Surgical excision of a solitary splenic lymphoma in one patient and medical therapy in another patient resulted in rapid normalization of the serum calcium and plasma 1,25-(OH)2D levels. These findings confirm an earlier observation that elevated plasma levels of 1,25-(OH)2D may occur in certain patients with lymphoma and suggest that this vitamin D metabolite may act as a humoral or systemic mediator of hypercalcemia. Proof that this is the case and identification of the source of 1,25-(OH)2D production will require further study.
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PMID:Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia. 387 Oct 92

We have purified peptides with PTH-like bioactivity from a rat Leydig cell tumor (H-500) and a human squamous cell carcinoma, both associated with a syndrome of humor-induced hypercalcemia. Tumor extracts were shown to be active in an in vitro renal cytochemical bioassay and in an in vitro osteosarcoma cell (UMR 108) adenylate cyclase assay; activity in both assays could be reduced by the PTH antagonist [norleucine-8,18,tyrosine-34]bovine PTH-(3-34)-amide. Partially purified extracts of both tumors and of rat tumor-conditioned culture medium were active in vivo in thyroparathyroidectomized rats in preventing hypocalcemia and increasing fractional phosphorus excretion and cAMP excretion. Ion exchange chromatography demonstrated that active peptides were basic in character. Employing reverse phase HPLC and gel permeation HPLC, active peptides of approximately 9,000 and 9,500 daltons were purified from extracts of the human and rat tumors, respectively, which had similar but not identical compositions. Two additional bioactive peptides were detected in rat tumor extract, and the more active had a mol wt of approximately 28,000. The results demonstrate that peptides that mimic PTH in a variety of in vivo and in vitro bioassays can be extracted from malignancies associated with hypercalcemia, that multiple molecular species may be detected in tumors that demonstrate PTH-like activity, and that at least one of these peptides may be similar in two tumors of highly divergent cell and species origin.
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PMID:Purification of peptides with parathyroid hormone-like bioactivity from human and rat malignancies associated with hypercalcemia. 394 72

An adenylate cyclase bioassay for parathyroid hormone (PTH) was evaluated in peripheral sera of ten normal subjects, 15 patients with various types of hypoparathyroidism, nine patients with malignancy-associated hypercalcaemia and 60 patients with primary or secondary hyperparathyroidism. The lower limit of detectability was 150 pg/ml in terms of synthetic human PTH (1-34). PTH-like bioactivity was not detected in normal subjects, in patients with surgical hypoparathyroidism, in patients with idiopathic hypoparathyroidism or in patients with malignancy-associated hypercalcaemia. Serum from one untreated pseudohypoparathyroid patient consistently contained PTH-like bioactivity. Bioactivity was detected in sera from 50% of patients with primary or secondary hyperparathyroidism. In two patients with secondary hyperparathyroidism calcium infusions suppressed this activity within 5 min. Both in primary and in secondary hyperparathyroidism there was a significant positive correlation between levels of PTH-like bioactivity, PTH immunoreactivity and the histological severity of the disease.
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PMID:An adenylate cyclase bioassay for parathyroid hormone: some clinical experiences. 397 62

A child with a pheochromocytoma had hypercalcemia but no evidence for excessive parathyroid hormone secretion from the parathyroid glands or the pheochromocytoma. Therapy with the catecholamine synthesis inhibitor metyrosine (alpha-methyltyrosine) reversed the catecholamine excess but had no effect on the hypercalcemia. Adrenalectomy promptly reversed the hypercalcemia. Extracts of the tumor contained a substance(s) that produced both potent in-vitro bone resorption and striking adenylate-cyclase-stimulating activity in renal cortical membranes. This stimulating activity was due to activation of the parathyroid hormone receptor/adenylate cyclase complex but was not due to parathyroid hormone. Our findings document hypercalcemia in association with pheochromocytoma and show that hypercalcemia occurred in the absence of previously proposed mechanisms. We also provide preliminary characterization of the presumed responsible substance(s) and suggest that this substance(s) may be related to that associated with the humoral hypercalcemia of malignancy.
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PMID:Hypercalcemia in pheochromocytoma. Evidence for a novel mechanism. 399 89

Urinary excretion of cyclic adenosine 3',5'-monophosphate (3',5'-AMP) was tested in normal subjects and patients with pseudohypoparathyroidism, idiopathic hypoparathyroidism, surgical hypoparathyroidism, and pseudopseudohypoparathyroidism under basal conditions and after a 15 min infusion of purified parathyroid hormone. Basal excretion of the nucleotide was less than normal in the patients with hypocalcemic disorders and greater than normal in pseudopseudohypoparathyroidism. Parathyroid hormone caused a marked increase in excretion of 3',5'-AMP in all subjects except those with pseudohypoparathyroidism; nine patients with this disorder did not respond to the hormone and four showed a markedly deficient response. Radioimmunoassay showed that parathyroid hormone circulated in increased amounts in plasma from patients with pseudohypoparathyroidism and became undetectable when serum calcium was increased above 12 mg/100 ml. Suppression of parathyroid hormone secretion by induction of hypercalcemia did not alter the deficient response to exogenous hormone. The results indicate that: (a) parathyroid hormone circulates in abnormally high concentrations in pseudohypoparathyroidism and secretion of the hormone responds normally to physiological control by calcium; (b) testing urinary excretion of 3',5'-AMP in response to infusion of purified parathyroid hormone appears to be an accurate and sensitive index for establishing the diagnosis of pseudohypoparathyroidism; and (c) the metabolic defect of the disorder can be accounted for by a lack of or defective form of parathyroid hormone-sensitive adenyl cyclase in bone and kidney.
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PMID:Pseudohypoparathyroidism: defective excretion of 3',5'-AMP in response to parathyroid hormone. 430 2

A possible association between the impairment of urinary concentrating ability and an impairment of the vasopressin-dependent cyclic AMP system in hypercalcemia was investigated in rat kidneys both in vivo and in vitro. The increases of urinary osmolality and negative free water clearance and the increase of urinary cyclic AMP excretion by vasopressin injection were significantly less in the hypercalcemic rats than in the control rats. The increase of cyclic AMP concentration by vasopressin in renal medullary tissue was significantly less in the slices obtained from the hypercalcem'c rats than in those obtained from the control rats. The activation of adenylate cyclase by vasopressin was significantly less in the group with an increased concentration of calcium in media than the control group, but phosphodiesterase activity was not affected by calcium concentration in the media. These data suggest that the impaired urinary concentrating ability in hypercalcemic kidneys is due at least in part to the direct inhibitory effect of calcium on the vasopressin-dependent cyclic AMP system at the level of adenylate cyclase in renal medulla.
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PMID:Pathogenic role of cyclic AMP in the impairment of urinary concentrating ability in acute hypercalcemia. 437 61

Three sulfur-free analogues of bovine parathyroid hormone (bPTH) containing D-amino acids were synthesized by the solid-phase method and their biological properties compared in an in vitro bioassay (rat renal adenylate cyclase assay), a receptor assay for parathyroid hormone (PTH) (canine renal membranes), and an in vivo bioassay (chick hypercalcemia assay). The analogue [Nle8,Nle18,D-Tyr34]-bPTH-(1-34)-amide, which was found to be more than 4 times as potent in vitro as unsubstituted PTH, is the most potent analogue of PTH yet synthesized. The enhanced potency was largely attributable to increased affinity for the PTH receptor. In vivo, however, this analogue was only one-third as potent as bPTH-(1-34). Cumulative evidence suggests that the nearly 15-fold decline in the relative potency when the compound was assayed in vivo is due to the substitution of norleucine for methionine. The other analogues, [D-Val2,Nle8,D-Tyr34]bPTH-(1-34)-amide and [D-Val2,Nle8,Nle18,D=Tyr34]bPTH-(2-34)-amide, were only weakly active in vitro and in vivo, indicating that substitution with D-amino acids at the NH2 terminus of PTH causes markedly diminished receptor affinity. In fact, the placement of a D-amino acid at the NH2 terminus is more deleterious to biological activity than is omission of amino acids at positions 1 and 2.
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PMID:Sulfur-free parathyroid hormone analogues containing D-amino acids: biological properties in vitro and in vivo. 627 93


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