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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A tumor-derived factor believed to cause hypercalcemia by acting on the parathyroid hormone (PTH) receptor was recently purified, cloned, and found to have NH2-terminal sequence homology with PTH. The 1-34 region of this protein was synthesized, evaluated for its postreceptor effects on the ROS 17/2.8 cell line, and its properties were compared to 1-34 PTH. Both 1-34 human humoral hypercalcemia factor (HCF) and 1-34 PTH stimulated adenylate cyclase with an effective concentration (EC)50 of approximately 1 nM. The extent of stimulation by both peptides was equally enhanced by dexamethasone. They both had a pronounced inhibitory effect on growth in the presence of dexamethasone, with an EC50 of approximately 0.1 nM, reduced alkaline phosphatase (AP) activity by approximately 70% in the absence of dexamethasone and by approximately 80% in the presence of dexamethasone with an EC50 of 0.03 nM, and when present at a concentration of 10 nM, reduced AP mRNA levels (estimated by Northern analysis) by approximately 80% in the presence or absence of dexamethasone. Thus, in addition to similar dose-response curves for adenylate cyclase stimulation, both HCF and PTH produced identical postreceptor effects in ROS 17/2.8 cells. These effects of HCF are probably mediated by the interaction of the tumor-derived factor with the PTH receptor.
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PMID:Comparison of postreceptor effects of 1-34 human hypercalcemia factor and 1-34 human parathyroid hormone in rat osteosarcoma cells. 283 Mar 17

The N-terminal fragment of human hypercalcemia factor (hHCF), hHCF-(1-34)NH2, has bioactivities similar to PTH in vitro and in vivo. Because it interacts with PTH receptors and is more potent than PTH in some systems, the hHCF sequence may provide interesting leads for the design of potent and selective PTH and hHCF antagonists. Based on the antagonist activity of [Tyr34]bovine PTH-(7-34)NH2 [( Tyr34]bPTH-(7-34)NH2), we synthesized the corresponding fragment of hHCF, hHCF-(7-34)NH2 and examined its properties in vitro. In the bone-derived rat osteosarcoma cell line ROS 17/2.8, hHCF-(7-34)NH2 and [Tyr34]bPTH-(7-34)NH2 were equipotent for inhibition of radiolabeled PTH-binding. In contrast, hHCF-(7-34)NH2 was 8-fold more potent that [Tyr34]bPTH-(7-34)NH2 for inhibiting PTH-stimulated cAMP production. hHCF-(7-34)NH2 also inhibited PTH-binding and PTH-stimulated adenylate cyclase activity in bovine renal cortical membranes: hHCF-(7-34)NH2 and [Tyr34]bPTH-(7-34)NH2 were equipotent in this system. In addition, hHCF-(7-34)NH2 antagonized hHCF-(1-34)NH2 action in both systems with similar inhibition constants. However, unlike the PTH analogue, hHCF-(7-34)NH2 (8 microM) was a weak partial agonist, producing a 2.4-fold increase in cAMP (5% of the maximal response) in ROS cells. This same system also detects agonism for [Nle8, 18Tyr34]bPTH-(3-34)NH2, another PTH partial agonist/antagonist. These results demonstrate that hHCF-(7-34)NH2 interacts with PTH receptors based in large part on the region which is not homologous to PTH, and suggest the utility of the ROS 17/2.8 cell system for identifying weak agonism of PTH and hHCF analogues in vitro.
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PMID:The 7-34-fragment of human hypercalcemia factor is a partial agonist/antagonist for parathyroid hormone-stimulated cAMP production. 283 81

This investigation addresses a theoretical concept of tumor pathogenesis proposed over 40 years ago, namely that malignancy-associated hypercalcemia can result from endocrine secretion by tumors of a PTH-like factor. These studies demonstrate that a fragment of hHCF alone, without added or tumor-secreted cofactors or hormones, can produce hypercalcemia and other biochemical abnormalities associated with HHM. The hypercalcemia can be generated by hHCF-(1-34)NH2 action on bone, although kidney and gut could contribute to the HHM syndrome when it occurs naturally. No other tumor-secreted peptide displays this biological profile. These studies establish one (PTH-like) mechanism by which human tumors could produce hypercalcemia. Furthermore, the finding that hHCF-(1-34)NH2 is more potent than PTH in some systems is of considerable interest for the future design of hormone analogs. A broad spectrum of biological properties of hHCF-(1-34)NH2, including production of components of the HHM syndrome, can be inhibited by a PTH antagonist. Because [Tyr-34]bPTH-(7-34)NH2 selectively and competitively occupies PTH receptors, our studies demonstrate formally that hHCF-(1-34)NH2 mediates some (and perhaps all) of its actions via receptors conventionally regarded as intended for interaction with PTH, but which actually may be present to allow for expression of bioactivity of both secreted proteins. Although some structural homology is shared by the two hormones and many contribute to interaction with receptors, the disparity in structure, especially within the 1-34 domains responsible for bioactivity in both hormones, is more pronounced. The similarity in biological profiles despite structural differences between hHCF and PTH is emphasized by the inhibitory action of [Tyr-34]bPTH-(7-34)NH2 against the tumor peptide even in the absence of much of the homologous region in the PTH antagonist. This investigation provides impetus for designing more potent antagonists, which must now be regarded more appropriately as inhibitors of both PTH and hHCF. Such antagonists may best be generated from hybrid structures of the two hormones. In any case, these studies establish a promising new approach to therapy of tumor-associated hypercalcemia.
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PMID:A tumor-secreted protein associated with human hypercalcemia of malignancy. Biology and molecular biology. 285 15

Peptides containing residues 1-34 of the human parathyroid hormone (PTH)-like hypercalcemic factor (hHCF), termed hHCF-(1-34)-NH2, produce effects similar to those of PTH in several biological systems in vitro and in vivo. However, there is conflicting evidence regarding the potency of hHCF on bone and, by implication, its role in calcium mobilization and the skeletal contribution to tumor-associated hypercalcemia. To resolve this conflict, the effects of infusing either hHCF-(1-34)-NH2 or a peptide containing residues 1-34 of bovine PTH [bPTH-(1-34)] into unrestrained thyroparathyroidectomized rats on a low calcium diet were compared. Direct effects on bone histology and serum calcium levels, which are totally dependent on calcium mobilization from bone in these animals, were examined. bPTH-(1-34) and hHCF-(1-34)-NH2 were equipotent in producing dose-dependent calcium mobilization from bone. At an infusion rate of 0.1 nmol/hr, both peptides produced hypercalcemia and extensive nephrocalcinosis. Histomorphometric analysis of tibiae from these animals after 48 hr of peptide infusion showed a dose-related increase in osteoclast number from 3-5 cells per mm2 at 0.01 nmol/hr to approximately equal to 32 cells per mm2 at 0.1 nmol/hr of hHCF or bovine PTH. These findings indicate that hHCF has a direct PTH-like effect on bone and, in this model system, the hHCF-(1-34)-NH2 is equipotent to bPTH-(1-34).
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PMID:Direct action of the parathyroid hormone-like human hypercalcemic factor on bone. 339 7

Parathyroid cells were obtained by collagenase digestion of 2 g of human parathyroid tissue obtained at surgery from a patient with end stage renal failure and hypercalcemia. Cells were placed into monolayer culture in supplemented Waymouth's MB752/1. Secretion of parathyroid hormone (PTH) from monolayer cultures was inhibited for 3 weeks by 2.5 mM compared to 0.5 mM calcium. The inhibition was 50% on day 3 of culture, and decreased to 19% by day 21. When cultures were incubated with [3H]leucine, radioactive PTH and COOH-terminal PTH fragments were secreted. Sequence analyses were performed on material in radioactive and immunoreactive peaks following gel filtration and high performance liquid chromatography of media. The results indicated that cleavage of PTH or fragments thereof occurred at the 23-24, 27-28, and 33-34 peptide bonds. NH2-terminal fragments of PTH were not detected in media.
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PMID:Structural analysis of parathormone fragments elaborated by cells cultured from a hyperplastic human parathyroid gland. 350 16

Hypercalcemic infantile renal tumors without bone metastases should be considered to be a heterogeneous tumoral entity. Histological and ultrastructural features, different from those of nephroblastoma, should not be exclusively linked with malignant rhabdoid tumors of the kidney. This is reported by the present case, which appears to be a cellular variant of mesoblastic nephroma and was successfully serially transplanted to nude mice. The causes of hypercalcemia in infantile renal tumors are probably related either to NH2-terminal parathormone or to prostaglandin E2 production by the tumoral cells.
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PMID:Hypercalcemic infantile renal tumors: morphological, clinical, and biological heterogeneity. 409 23

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

In exceptional cases, acromegaly develops as the clinical expression of an ectopic secretion of Growth Hormone (GH) or Growth Hormone-Releasing Factor (GRF), tumorous in origin. In the present report, we describe an instance of acromegaly caused by the secretion of GRF from a voluminous pancreatic tumor. The resection of this tumor resulted in a temporary disappearance of the biological and clinical symptoms of acromegaly, which then reappeared in conjunction with a rise in plasma GRF. From this pancreatic tumor, substances displaying a potent GRF activity were isolated and characterized. Amino acid analyses revealed that they were related to 3 peptides containing respectively 44, 40 and 37 aminoacids. The largest (hp GRF (1-44)-NH2) referred as hp GRF or somatocrinin is considered to be the primary molecule. The pancreatic tumor was multisecreting as proved by high plasma levels of somatostatin, pancreatic polypeptide and glucagon, normalized after the tumor removal, taken together with the immunocytochemical demonstration of the presence of these peptides in the tissue and with the isolation of somatostatin. In contrast hypercalcemia associated with an elevated plasma level of IR-PTH was unmodified by tumor removal. Diagnosis of acromegaly as ectopic endocrine syndrome will probably be facilitated by plasma GRF radioimmunoassay, as a result of production of anti synthetic GRF antibodies.
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PMID:[Acromegaly, clinical expression of the production of growth hormone releasing factor in pancreatic tumors]. 643 Feb 7

Nitrogen balance was studied in 4 patients with uremia during treatment with a protein-reduced diet (20 g) supplemented with either essential amino acids and histidine or a mixture of keto analogues of five of the essential amino acids and essential amino acids. 3 patients completed the study. Nitrogen balance was negative on the diet only and was improved with both forms of supplementation. However, supplementation with the keto acids did not offer any advantage over the conventional essential amino acid supplementation. 1 patient developed serious hypercalcemia during treatment with the keto acid supplementation.
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PMID:Nitrogen balance studies in patients with uremia during treatment with protein-reduced diet and supplementation with essential amino acids or keto acids. 670 48

The effect of phosphate deprivation on urinary acidification was investigated in rats fed a phosphate-deficient diet and in control rats fed the same diet supplemented with phosphate. Phosphate-deprived animals developed hypophosphatemia, hypercalcemia, and hypophosphaturia, but failed to develop hyperchloremic metabolic acidosis following 30 or 60 days of phosphate deprivation. Baseline urine pH was significantly higher in phosphate-deprived rats than in controls, but baseline urine HCO3 excretion was not significantly different between the two groups. The pattern of HCO3 reabsorption in phosphate-deprived rats was identical to that of controls at both low and high plasma HCO3 levels. During chronic NH4Cl administration, both 30- and 60-day phosphate-deprived rats had a sigificantly higher minimal urine pH and lower titratable acid and net acid excretion than seen in controls. NH4 excretion was significantly lower than controls in the 60-day phosphate-deprived rats only. During Na2SO4 administration the minimal urine pH was significantly lower in controls than in phosphate-deprived rats, but there was overlap of urine pH values. At comparable levels of urine pH, NH4 excretion was significantly lower in phosphate-deprived rats than in controls. Phosphate-deprived rats were able to raise urine-blood CO2 pressure to the same levels as controls during both HCO3 loading and Tris buffer administration. Phosphate-deprived rats had greater extrarenal buffering capacity than controls as evidenced by a lower decline in blood pH and HCO3 during HCl infusion in phosphate-deprived rats. These data demonstrate that phosphate deprivation is associated with distal acidification defect, impaired NH3 excretion, and increased extrarenal buffering capacity. The increased availability of buffer in phosphate deprivation may play an important role in acid-base homeostasis in this condition.
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PMID:Distal acidification defect induced by phosphate deprivation. 741 57


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