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)

Murine gamma-interferon (MuIFN-gamma) is a potent inhibitor of bone resorption induced by interleukin 1 and parathyroid hormone-related protein in vitro. To investigate whether MuIFN-gamma is also effective in vivo, the cytokine was injected s.c. into hypercalcemic, tumor (EC-GI)-bearing nude mice, in which parathyroid hormone-related protein and interleukin 1 alpha are synergistically responsible for causing humoral hypercalcemia. When MuIFN-gamma was injected s.c. at a dose of 1 to 20 x 10(4) units for 5 days consecutively, serum calcium concentrations in the tumor-bearing mice decreased in a dose-dependent manner. The minimal effective dose was 5 x 10(4) units/mouse. Unlike calcitonin, which decreased the serum calcium concentration for only 1 to 2 days despite continuous daily injections, MuIFN-gamma decreased it for more than 7 days even after the injections had been stopped. Human gamma-interferon was completely ineffective. The decrease in serum calcium concentration was accompanied by a decrease in urinary calcium excretion. Histological examination of the femur revealed a decreased number of osteoclasts in the MuIFN-gamma-treated mice. Furthermore, MuIFN-gamma, when injected into nude mice or normal mice at a dose of 15 x 10(4) units for 3 days, almost completely abolished the formation of multinucleated osteoclast-like cells in vitro. These findings suggest that MuIFN-gamma suppresses the formation and maturation of osteoclasts and inhibits osteoclastic bone resorption, resulting in the prolonged decrease of serum calcium concentration seen in hypercalcemic, tumor-bearing nude mice. Therefore, bone resorption inhibitors like MuIFN-gamma, which ameliorate humoral hypercalcemia without an escape phenomenon, are potentially useful for the treatment of malignancy-associated hypercalcemia.
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PMID:Prolonged decrease of serum calcium concentration by murine gamma-interferon in hypercalcemic, human tumor (EC-GI)-bearing nude mice. 172 16

Parathyroid hormone-related protein (PTHrP) plays a major role in the pathogenesis of malignant hypercalcemia, but has also been found in fetal and adult non-neoplastic tissues. Among them, lactating mammary gland was shown to produce PTHrP, and high levels of PTHrP were measured in milk. However, the regulation of PTHrP production by breast cells is still unknown. Primary cultures of mammary cells isolated from rat lactating glands were grown on collagen gels in an insulin/epidermal growth factor (EGF)-supplemented medium. Under these conditions, mammary cells displayed an epithelial phenotype and their number increased more than twofold after 1 week in culture. At that time, the cells were capable of producing immunoreactive PTHrP (range: 25 to 150 pg/10(5) cells x 24 h) and PTH-like bioactivity, as indicated by a 60% increase in cyclic adenosine monophosphate (cAMP) production induced by mammary epithelial cell conditioned medium in the PTH-responsive osteoblast-like UMR-106 cell line. When cell proliferation was hindered by lowering plating density, by removing medium supplements, or by adding transforming growth factor (TGF)-beta, a well-known autocrine inhibitor of mammary epithelial cell growth. PTHrP production was increased. In contrast, the omission of EGF or addition of specified anti-EGF antibodies decreased PTHrP production. In conclusion, primary cultures of mammary epithelial cells isolated from lactating rat were shown for the first time to produce PTHrP in vitro. This production was higher in the presence of EGF and could be modulated by cell growth rate.
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PMID:Parathyroid hormone-related protein production by primary cultures of mammary epithelial cells. 173 34

Parathyroid hormone-related protein (PTHrP), which is responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy, has recently been identified in several normal tissues. Because PTHrP, like parathyroid hormone (PTH), is known to exhibit vasodilatory properties, we investigated the expression and regulation of PTHrP mRNA in cultured rat aortic smooth muscle cells (SMC). We report here that PTHrP mRNA is expressed in SMC and is markedly induced by serum in a time- and concentration-dependent fashion. Addition of 10% fetal calf serum to serum-deprived, confluent cells, resulted in a marked induction of PTHrP mRNA by 2 h with a peak at 4-6 h. PTHrP was detected in SMC by immunocytochemistry and radioimmunoassay of conditioned medium, and was shown to be up-regulated within 24 h after the addition of serum. The serum induction of PTHrP mRNA was blocked by actinomycin D and by cycloheximide indicating the need for protein synthesis to evoke the serum effect on PTHrP gene transcription. In addition, treatment with dexamethasone, which has been previously shown to reduce the constitutive expression of PTHrP in human cancer cells, also blunted the serum induction of PTHrP mRNA in SMC. Treatment of quiescent cells with the serum mitogens platelet-derived growth factor or insulin-like growth factor-I had no effect on PTHrP, whereas the vasoactive peptides endothelin, norepinephrine and thrombin stimulated PTHrP expression. Exogenous addition of recombinant PTHrP-(1-141) had no significant effect on SMC DNA synthesis as measured by [3H]thymidine incorporation. In summary, the abundance of PTHrP mRNA and the characteristics of its regulation in SMC suggest a major role for PTHrP as a local modulator in vascular smooth muscle.
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PMID:Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation. 175 45

A region-specific radioimmunoassay has been employed to measure levels of immunoreactive parathyroid hormone-related protein(50-69) (iPTHrP(50-69)) in patients with tumour-induced hypercalcaemia (TIH). This assay is based on an antiserum raised against synthetic human PTHrP(50-69). The assay showed no cross-reactivity with human or bovine parathyroid hormone(1-84). The effect of a single dose (60 mg) of pamidronate was studied in 25 consecutive patients with TIH. All were rehydrated prior to treatment. All but 2 patients (8%) became normocalcaemic after treatment; both of these had very high levels of iPTHrP(50-69). Time to achieve normocalcaemia, as an index of relative resistance to pamidronate, correlated positively with pretreatment level of iPTHrP(50-69). Absence of radiological evidence of bone metastases also predicted relative resistance to pamidronate. In this study, iPTHrP(50-69)-induced osteoclastic bone resorption was a more important mechanism in the causation of TIH than PTHrP-induced renal reabsorption of calcium as assessed by the renal thresholds for calcium and phosphate.
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PMID:Parathyroid hormone-related protein(50-69) and response to pamidronate therapy for tumour-induced hypercalcaemia. 178 72

PTHrP, a newly characterized peptide is responsible for humoral hypercalcemia of malignancy in squamous cancers. It is also expressed by a variety of normal tissue and might have growth factor propriety. It is expressed by lactating breast and is frequently present in breast cancer. Although it is responsible for humoral hypercalcemia in an animal model of breast cancer its role in breast cancer hypercalcemia is still putative. The possibility that it might be one of the autocrine growth factors implicated in breast cancer cell proliferation has been suggested.
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PMID:Parathyroid hormone related protein (PTHrP) and breast cancer. 181 3

Metabolic disturbances of Na, K, Ca and glucose as paraneoplastic syndrome were reviewed on the basis of recent progress of such areas. These abnormalities usually occur due to the production of hormones or other physiologically active substances by tumor tissues. Hyponatremia is the most common abnormality of Na metabolism in patients with cancers such as lung cancer, malignant lymphoma, thymoma and so on. Usual cause of hyponatremia as paraneoplastic syndrome is inadequate secretion of Antidiuretic Hormone (SIADH), which brings dilution hyponatremia associated with water intoxication. Recently hyponatremia due to abnormal secretion of atrial natriuretic peptide has been noted. Ca metabolism disturbance associated with cancer is usually observed as hypercalcemia and it is said that such hypercalcemia is seen in about 10% of cancer patients. Main cause of hypercalcemia associated with cancer is local osteolytic hypercalcemia (LOH) due to bone metastasis or humoral hypercalcemia of malignancy (HHM). The most common etiology of HHM is the production of Parathormone (PTH) related peptide (PTH-rP) massively secreted from cancer tissues. PTH-rP has been recently well investigated and its molecular, mRNA and gene structure have been already determined. The progress of this area is very rapid and PTH-rP will be assayed in the clinical laboratory in near future. As for glucose metabolism disturbance as paraneoplastic syndrome, hypoglycemia is the most common abnormality. This type of hypoglycemia has been noted in relation with excessive production of somatomedin.
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PMID:[Metabolic disturbance as paraneoplastic syndrome]. 182 8

The biological properties of a new synthetic analog of parathyroid hormone-related protein [PTHrP-(7-34)NH2] were examined in vivo using a well characterized thyroparathyroidectomized (TPTX) rat model. The phosphaturic and urine cyclic AMP response induced by infusion of PTHrP-(1-34)NH2 (0.16 nmol/h) was inhibited by 70% (P less than 0.01, n = 6) by co-infusion of PTHrP-(7-34)NH2 at a 10-fold molar excess (1.6 nmol/h). The 7-34 PTHrP analog also antagonized the PTHrP-(1-34)NH2-induced hypercalcemia and rises in blood 1,25-dihydroxyvitamin D concentrations. However, when infused alone at a higher dose rate (8 nmol/h), PTHrP-(7-34)NH2 displayed significant PTH agonist activity. This profile contrasts to that of [Tyr-34]bPTH-(7-34)NH2 which is comparatively less potent (10-20-fold) with respect to its antagonist activity but has no appreciable agonist activity in vivo.
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PMID:A 7-34 analog of the parathyroid hormone-related protein has potent antagonist and partial agonist activity in vivo. 185 Jun 33

Interleukin (IL)-4 inhibits bone resorption. In the present study, the effect of IL-4 on hypercalcemia in nude mice under two experimental conditions was assessed. IL-4 inhibited plasma calcium elevation induced by parathyroid hormone-related protein (PTHrP) infusion. In hypercalcemic nude mice bearing PTHrP-producing tumors, IL-4 lowered plasma calcium levels to almost the normal range. These results indicate that IL-4 blocks PTHrP-induced hypercalcemia in vivo.
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PMID:Interleukin-4 blocks parathyroid hormone-related protein-induced hypercalcemia in vivo. 185 25

Malignancy is the most frequent cause of hypercalcemia in hospitalized patients. The pathophysiology of hypercalcemia of malignancy (HM) is complex. Increased bone resorption is involved in most cases caused either by extensive local bone destruction or by humoral factors. Tumor extracts from patients with humoral hypercalcemia of malignancy (HHM) often contain PTH-like bioactivity. Recently, cDNAs coding for a PTH-related protein (PTH-rP) has been cloned. The N-terminal amino acid sequence of this protein shows a considerable homology with human PTH. However, other bone resorbing factors including prostaglandins, transforming growth factors, colony stimulating factors, leucocyte cytokines and 1,25-dihydroxyvitamin D may be involved in different types of malignancy. HM is usually progressive with troublesome symptoms and a high mortality. Several treatment alternatives are available including rehydration, bisphosphonates, calcitonin, plicamycin, phosphate, and glucocorticoids. Others are under investigation. Treatment should be individualized taking into account the pathophysiological mechanisms involved, the extent of hypercalcemia and renal failure, and the prognosis related to the malignant disease.
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PMID:Hypercalcemia of malignancy: pathophysiology, diagnosis and treatment. 188 26

The infiltrated tissues from seven West Indian patients with HTLV-1 positive adult T cell lymphoma/leukaemia (ATLL) have been analysed by immunocytochemical techniques for the presence of immunoreactive parathyroid hormone-related protein (PTHrP), a hormonal mediator of humoral hypercalcaemia of malignancy. Six of the seven were hypercalcaemic at some stage of the course of their disease. Four of the six evaluable patients showed evidence of specific cellular and extracellular expression of PTHrP protein in neoplastic tissues. This finding suggests that PTHrP may be involved in the production of hypercalcaemia in at least some cases of T cell lymphoma - proof of a causal relationship however must await the demonstration of tissue release of PTHrP resulting in raised circulating hormone levels.
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PMID:Immunocytochemical demonstration of PTHrP protein in neoplastic tissue of HTLV-1 positive human adult T cell leukaemia/lymphoma: implications for the mechanism of hypercalcaemia. 191 Dec 23


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