UMLS:C0020437 - FACTA Search

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

Gallium (Ga) is an effective treatment for the hypercalcemia of malignancy. The mechanism of action of the metal in blocking bone resorption in humans is not well understood. This paper examines the effect of Ga on the in vitro formation of hydroxyapatite (HA) in three test systems that have possible biological relevance in a pH-stat at pH 7.4, 37 degrees C, and 0.15 M NaCl: (1) the direct precipitation of HA; (2) the transformation of amorphous calcium phosphate to HA; and (3) the growth of HA seeds. In addition, the effect of Ga on HA solubility was measured at pH 5.0, the approximate pH of osteoclastic bone resorption. Ga decreased the HA formation and/or growth kinetics in a dose-related manner in all three test systems. In addition, the time to the onset of HA formation was increased in systems 1 and 2. Also, the adsorption of Ga on the surface of HA crystals was measured. Ga reduced the dissolution kinetics of HA compared with Ga-free control. The mechanism reported herein--the significant adsorption of Ga on forming and growing HA nuclei and on the surface of HA crystals--is believed to be responsible for the effects of the metal on HA proliferation and solubility. Accumulation of the metal on newly formed metaphyseal bone can now be explained by this adsorption of Ga. These in vitro results partly explain the in vivo action of Ga in treating hypercalcemia by decreasing bone apatite solubility.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of gallium on the in vitro formation, growth, and solubility of hydroxyapatite. 255 Jan 17

This article covers considerations in the etiologies and therapy of hypercalcemia. The differential diagnosis of hypercalcemia is discussed, with particular emphasis on primary hyperparathyroidism and the hypercalcemia of malignancy. Clinical features of hypercalcemia are also discussed. Therapy of hypercalcemia is considered from the point of view of principles and general and specific measures, with emphasis on a pathophysiologic rationale for therapy.
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PMID:Etiologies and therapy of hypercalcemia. 266 80

Hypercalcaemia in malignancy is a major clinical problem. It contributes significantly to morbidity and mortality and can present difficult diagnostic and management dilemmas. Direct bony invasion by tumour cells rather than humorally mediated hypercalcaemia is probably the most common cause of malignant hypercalcaemia. Yet even in this situation the mechanism of bone resorption or the reason that the normal homeostatic mechanisms cannot cope with the calcium load are poorly understood. It is likely that the humoral and paracrine factors produced by tumours which result in hypercalcaemia or in osteosclerotic bone metastases, are interposing themselves into the normal regulatory processes and deranging them. Humoral hypercalcaemia of malignancy is an important model for studying these questions, and it also provides some insight into the normal regulation of bone turnover. This review will examine the animal models and human syndromes of malignant hypercalcaemia and show how animal models, although helpful, fail to delineate the relative importance of the various potential humoral factors. A most interesting recent development in this area is the description of a new hormone, the parathyroid hormone-related peptide, which may explain many of the cases of humoral hypercalcaemia of malignancy. It is also a useful model with multiple sites of action within the bone and calcium homeostatic process. The active hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3, may also be involved in a small proportion of cases, but again it is a useful model of some of the factors that may operate. Of considerable interest are the tumour derived factors, such as the transforming growth factors, and the cytokines, such as tumour necrosis factors, interleukins, and haemopoietic colony stimulating factors. Prostanoids are seldom of major importance, but may be important in certain tumour types. Osteosclerotic metastases, although seldom associated with hypercalcaemia, may provide insight into osteoblast regulating factors. Treatment of hypercalcaemia is discussed to show ways in which response to treatment may shed light on underlying pathophysiological mechanisms. Most effective treatments have many potential modes of action, and further study of the interactions of these agents and tumour types may help to unravel some of the enigmas in this human syndrome. The major advances in this complex problem involve the realisation of the necessity of multiple sites of action, including renal calcium handling as well as relative increases in bone resorption and/or intestinal calcium absorption.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypercalcaemia of malignancy. 266 84

Humoral hypercalcemia of malignancy is a common cause of malignancy-associated hypercalcemia. This syndrome is caused by the elaboration of a tumor-derived factor or factors that induce intense bone resorption and increased renal tubular calcium reabsorption. Recently, the PTHrP has been isolated from tumors associated with HHM, and a single copy gene directing its synthesis has been identified on human chromosome 12. Analysis of mRNA from tumor-derived tissue suggests a complex pattern of hybridizing transcripts, implicating alternative processing of this gene. However, the circulating form or forms of the protein have yet to be determined. Synthetic amino-terminal polypeptides of PTHrP in vivo and in vitro reproduce all of the essential features of HHM. Preliminary studies suggest that neutralizing antisera to this protein reverse the hypercalcemia in experimental models for HHM. Thus, it appears likely that this protein has a central pathogenic role in HHM. The development of antisera to this protein will aid in the detection and diagnosis of malignancy-associated hypercalcemia. Antagonists to this molecule may be helpful in treating this disorder.
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PMID:Humoral hypercalcemia of malignancy. The role of parathyroid hormone-related protein. 267 73

Neoplasms of the parathyroid glands are uncommon in all species of laboratory and domestic animals, but occur in low incidence in rats, Syrian hamsters, and dogs and rarely in mice. Proliferative lesions of the parathyroid gland include hyperplasia (diffuse and focal), adenomas, and carcinomas. The tumors may be functional or nonfunctional. Trophic atrophy of remaining parathyroid tissue is present around functional tumors. Humoral hypercalcemia of malignancy (HHM) is a syndrome that occurs in human and animal patients with certain malignant neoplasms and is characterized by hypercalcemia, hypophosphatemia, and increased osteoclastic bone resorption. The syndrome is thought to be due to the release of parathyroid hormone (PTH)-like factors by the tumor cells which bind to PTH receptors in bone and kidney and result in the clinical manifestations of HHM. Parathyroid hormone-related protein (PTHrP) is a newly purified and sequenced protein which originated from human tumors associated with HHM. PTHrP has been shown to stimulate in vitro and in vivo effects similar to PTH-like proteins isolated from tumors associated with HHM. Well characterized animal models of HHM include a rat Leydig cell tumor line (Rice-500), the rat Walker mammary carcinosarcoma, and the canine apocrine adenocarcinoma. All 3 models have been found to contain 3 biologic activities which are thought to be important in the pathogenesis of HHM, viz., in vitro bone resorbing activity, adenylate cyclase-stimulating activity of bone and kidney cells, and transforming growth factor activity. The first 2 activities are due to PTH-like proteins which are able to compete for binding to the PTH receptor. The complete spectrum of functional disturbances in patients with HHM may be the result of the combined effects of a PTH-like protein (i.e., PTHrP) and transforming growth factors.
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PMID:Tumors of the parathyroid gland and circulating parathyroid hormone-related protein associated with persistent hypercalcemia. 267 85

Many factors, such as interleukin 1, TGF alpha, tumor necrosis factor alpha and beta, and PGs, have been implicated in etiological roles in HHM (Martin and Mundy, 1987). Much interest in the past has also centered upon the likelihood of ectopic secretion of PTH in this condition. We have purified a protein (PTHrP) implicated in HHM from a human lung cancer cell line (BEN). Full-length cDNA clones have been isolated and were found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino acids were identical with human PTH, although antisera directed to the NH2 terminus of PTHrP do not recognize PTH; this homology is not maintained in the remainder of the molecule. PTHrP therefore represents a previously unrecognized hormone, possibly related to the PTH gene by a gene duplication mechanism. In support of this notion, the PTHrP gene has been localized to the short arm of chromosome 12; it is believed that chromosome 11, containing the PTH gene, and chromosome 12 are evolutionarily related. In addition, the human PTHrP gene has been isolated, characterized, and shown to have a similar intron--exon organization as the PTH gene. It is possible that the original ancestral gene is indeed the PTHrP gene; resolution of this question awaits studies in lower species. Peptides synthesized to the predicted protein sequence have enabled detailed structure-function studies that have identified NH 2-terminal sequences to be responsible for the biological effects of the molecule. Antibodies raised against the various synthetic peptides have led to the immunohistochemical localization of PTHrP in many human squamous cell carcinomas as well as in a subpopulation of keratinocytes of normal skin. The availability of these antibodies has opened the way for the development of a radioimmunoassay to detect PTHrP in the sera of cancer patients at risk of developing hypercalcemia. The recent characterization of PTHrP-like activity in the ovine fetus suggests some physiological function for PTHrP. It is possible that PTHrP, as the fetal counterpart of PTH, has the role of maintaining the maternal-fetal calcium gradient. The isolation and characterization of PTHrP have added to our understanding of the mechanisms of hypercalcemia and may contribute to the understanding of other metabolic bone diseases, such as osteoporosis and Paget's disease. Finally, and perhaps most importantly, PTHrP may play a hitherto unrecognized role in normal cell physiology.
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PMID:Parathyroid hormone-related protein: isolation, molecular cloning, and mechanism of action. 268 46

Hypercalcemia results from an imbalance between the fluxes of calcium (Ca) entering and leaving the extracellular space. The two most important influxes are the net intestinal Ca absorption and the net skeletal Ca resorption, whereas the renal excretion represents the main route of elimination. When produced in excess, various factors, particularly calciotropic hormones and cytokines, can disturb the Ca fluxes at intestinal, skeletal and renal tubular sites. If the excessive production of these substances cannot be controlled by surgical or pharmacological means, the next most rational therapeutic strategy should be aimed at correcting those Ca fluxes which are abnormally increased. In hypercalcemia of malignancy (HM), an augmentation in net bone resorption (BR) is observed in most patients. However, a sustained stimulation in tubular Ca reabsorption (TRCa), despite correction of volume depletion by saline infusions, may not only contribute to the hypercalcemia, but in some cases it appears to be the prevailing disturbance. In these patients the effects of the antiresorbing agent clodronate (500 mg/8 h iv in one single infusion) is incomplete, despite the normalisation of BR. Thus, administration of an antiresorbing agent, such as clodronate, is the treatment of choice in HM with elevated BR and normal TRCa. It should be given with other therapeutic agents when a sustained increase in TRCa is the prevailing mechanism for hypercalcemia. In this regard, experimental studies suggest that the agent WR-2721, which specifically inhibits TRCa could be an effective drug for rapidly lowering plasma Ca in HM with high TRCa.
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PMID:Management of hypercalcemia in relation to pathophysiology. 282 40

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

We have studied the administration of both oral and intravenous dichloromethylene diphosphonate (Cl2MDP) in patients with hypercalcemia and/or hypercalciuria due to increased bone resorption in the setting of multiple myeloma (N = 16) or chronic lymphocytic leukemia (N = 1). The effectiveness of 1600 mg of oral Cl2MDP twice daily was studied in 14 subjects with refractory multiple myeloma, active osteolytic disease and either persistent hypercalciuria (urinary Ca greater than 200 mg per g creatine on a low Ca intake) or hypercalcemia (serum Ca greater than 11.0 mg/dl), in a double-blind, placebo-controlled, 16 week-long trial. Of the 12 patients who received Cl2MDP (2 died in the placebo phase), 11 had marked reductions in urinary calcium (P less than 0.001), which fell into the normal range in 9. Urinary hydroxyproline decreased significantly in 8. Eight of the 11 responders also appeared to have decreases in bone pain associated with Cl2MDP therapy. Similar results were found when this protocol was used in a study of 10 women with breast cancer metastatic to bone. In addition, intravenous Cl2MDP was studied in 12 patients with hypercalcemia of malignancy, of whom 2 had multiple myeloma and 1 had chronic lymphocytic leukemia (CLL) associated with extensive osteolytic bone destruction. We gave 2.5 mg/kg on the first treatment day and 5 mg/kg daily thereafter for up to six more days. Serum calcium fell to normal after a mean of four days in the three patients with hematologic malignancies as well as in eight of the nine with solid tumors. Both urinary Ca and OHP also declined significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dichloromethylene diphosphonate action in hematologic and other malignancies. 296 56

The effect of a low calcium diet, mithramycin, or dichlorodimethylene bisphosphonate were evaluated in nude mice with humoral hypercalcemia of malignancy associated with the transplanted canine adenocarcinoma (CAC-8). Low calcium (0.01%) diet significantly reduced serum calcium levels in hypercalcemic nude mice and reduced urine calcium excretion to control levels. Mithramycin (8 mg/kg) decreased serum calcium concentration and urine calcium excretion to the range of control non-tumor-bearing nude mice at day 5 after a single injection, but there was no change in the number of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from CAC 8-bearing nude mice after mithramycin administration were decreased in size, had small ruffled borders, and increased relative size of clear zones. Dichlorodimethylene bisphosphonate (Cl2MDP) (45 mg/kg) partially reduced serum calcium concentration of hypercalcemic tumor-bearing nude mice, decreased urine calcium excretion to control levels, and markedly reduced the numbers of tartrate-resistant acid phosphatase-positive osteoclasts in lumbar vertebrae. Osteoclasts from Cl2MDP-treated nude mice were smaller and had a reduced frequency of ruffled borders than saline-treated hypercalcemic nude mice. In vitro bone resorption induced by CAC-8 extract was significantly reduced by Cl2MDP and mithramycin. The results of these investigations suggest that the hypercalcemia and hypercalciuria associated with HHM in nude mice with CAC-8 are the combined result of altered calcium homeostasis in the bone, kidney, and intestine. Chemotherapeutic agents that specifically affect only bone or feeding a low calcium diet alone may not completely ameliorate the hypercalcemia of HHM.
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PMID:The effect of low calcium diet, mithramycin, and dichlorodimethylene bisphosphonate on humoral hypercalcemia of malignancy in nude mice transplanted with the canine adenocarcinoma tumor line (CAC-8). 297 5

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