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)

The extensive chromatographic characterization of four parathyroid hormone (PTH)-like proteins in a human bronchial carcinoid tumour associated with humoral hypercalcaemia and severe osteitis fibrosa is described. PTH-like bioactivity was detected in acetic acid extracts of the tumour using an in-vitro osteo-sarcoma cell bioassay. The active tumour proteins were positively charged at physiological pH and had apparent Mr of approximately 29,000, 16,000, 4000-9000 and less than 4000. The proteins were immunologically distinct from PTH, but each stimulated PTH-sensitive adenylate cyclase in cultured osteoblastic cells. There was no evidence of PTH gene expression by the tumour. These proteins represent different molecular forms of PTH-related protein.
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PMID:Multiple forms of parathyroid hormone-like proteins in a human tumour. 254 21

Peptides containing residues 1-34 of parathyroid hormone-related protein (PTHrP) and of bovine parathyroid hormone (bPTH), and recombinant full-length PTHrP(1-141) were infused i.v. into anaesthetized thyroparathyroidectomized rats to compare their action and potency on the renal handling of calcium, phosphate and cyclic AMP (cAMP) in vivo. All three peptides decreased the excretion of calcium and increased the excretion of phosphate and cAMP in the urine, with PTHrP(1-34) and PTHrP(1-141) having virtually equipotent effects. Thus the essential requirements for the major physiological activity of PTHrP on the kidney are contained within the 34 amino-terminal amino acids. For all three peptides, the lowest infusion rate that increased phosphate and cAMP excretion was 0.01 nmol/kg per h, whereas the lowest infusion rate that decreased calcium excretion was 0.025 nmol/kg per h for the PTHrP peptides and 0.1 nmol/kg per h for bPTH(1-34). The response to the PTHrP peptides was maximal at an infusion rate of 0.1 nmol/kg per h for both calcium and phosphate. Since the kidney is either equally sensitive to PTHrP and bPTH(1-34), or more sensitive to PTHrP than to bPTH(1-34), the hypercalcaemia of humoral hypercalcaemia of malignancy may develop because uncontrolled secretion of PTHrP increases the renal reabsorption of calcium to such an extent that even a modest increase in the inflow of calcium into the blood raises plasma calcium concentration.
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PMID:Actions of parathyroid hormone-related protein on the rat kidney in vivo. 254 49

Expression of a parathyroid hormone-like protein (PLP), which is associated with hypercalcemia in malignancy, has recently been localized to normal lactating mammary tissue. We examined the possibility of an extramammary role of PLP by measuring its levels in serum and milk of lactating women. The levels of PLP by radioimmunoassay in serum of lactating and nonlactating women were indistinguishable [4.2 +/- 1.8 and 3.6 +/- 1.0 pg equivalents (eq) of PLP-(1-34) amide per ml, respectively]. As PLP was undetectable in some serum samples, this result does not exclude the possibility that lactation results in a small increase in serum levels of PLP. In contrast, high concentrations of immunoreactive PLP [40,000-75,000 pg eq of PLP-(1-34) amide per ml] and correspondingly high concentrations of bioactive PLP were found in human, rat, and bovine milk. A variety of processed bovine milk products had a PLP content similar to that of fresh bovine milk, whereas infant formulas had lower concentrations, ranging down to undetectable. Although the physiological role of PLP in lactation is unknown, the data establish the presence of PLP in milk and suggest the possibility that PLP may be important in neonatal calcium homeostasis.
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PMID:High levels of a parathyroid hormone-like protein in milk. 255 Sep 32

Hypercalcemia occurred in a patient with leiomyosarcoma when multiple lung metastases developed. Despite normal plasma parathyroid hormone (PTH) levels and low 1,25-dihydroxyvitamin D, this hypercalcemic patient had a marked hypercalciuria and phosphaturia associated with an increased excretion of nephrogenous cyclic AMP (NcAMP). Administration of cisplatin ameliorated both the hypercalcemia and hypercalciuria without any reduction in tumor size of NcAMP excretion. Terminally, acute pancreatitis occurred producing a profound hypocalcemia. In the extract of tumor tissue obtained post mortem, bioactivity stimulating the generation of cyclic AMP in osteogenic cells was demonstrated along with the immunoreactive PTH-related protein (PTH-rP). the first report of a solid non-epithelial malignancy producing PTH-rP and associated with humoral hypercalcemia of malignancy. The hypercalcemia in this case caused acute pancreatitis, which led to a profound hypocalcemia.
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PMID:A case of leiomyosarcoma associated with humoral hypercalcemia of malignancy: demonstration of biological and immunological activities of parathyroid hormone-related protein in the tumor extract. 255 69

A protein responsible for the biochemical syndrome similar to primary hyperparathyroidism associated with certain tumors has been recently characterized and its effects at the level of bone and kidney reported. However, the relative role of tubular reabsorption of calcium (Ca) and bone resorption in the pathogenesis of hypercalcemia induced by this factor is still debated. We investigated the effects of a synthetic amino-terminal fragment of parathyroid hormone-related protein [PTHrP-(1-34)] administered chronically by intraperitoneal osmotic minipumps in thyroparathyroidectomized (TPTX) rats. Clearance studies performed on day 6 of treatment after a 24 h fast revealed an increase in renal tubular reabsorption of Ca and a decrease in renal tubular reabsorption of phosphate (Pi), accompanied by an increase in cAMP excretion. PTHrP-(1-34) (90 pmol/h) stimulated bone resorption as evaluated by an increment in fasting urinary Ca excretion. Although the bone resorption inhibitor aminopropylidene diphosphonate fully corrected urinary Ca excretion and reduced plasma Ca from 3.04 +/- 0.07 to 2.44 +/- 0.21 mM (p less than 0.05), this latter value remained considerably higher than in TPTX control rats (1.54 +/- 0.12 mM, p less than 0.01). In contrast, when the agent WR-2721, which is known to decrease the renal tubular reabsorption of Ca by a PTH-independent mechanism, was given, a further drop in plasma Ca and an increase in urinary Ca excretion were observed. These findings are similar to those found in animals implanted with the hypercalcemic Leydig cell tumor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of bone and kidney in parathyroid hormone-related peptide-induced hypercalcemia in rats. 255 91

The pathogeneses of hypercalcemia and hypophosphatemia which developed in a patient with metastatic invasive ductal breast carcinoma were studied. The patient had low plasma levels of immunoreactive parathyroid hormone (PTH) and 1,25(OH)2D, increased nephrogenous cyclic adenosine monophosphate (cAMP) excretion and low TmPO4/GFR, suggesting the presence of humoral PTH-like activity. The tumor extract showed activities which would stimulate bone resorption in vitro and cAMP generation in the osteogenic cell line, MC3T3 E1, and in the rat kidney cortex. In addition, the extract stimulated epidermal growth factor (EGF)-independent colony formation of the NRK 49F cells in soft agar, and inhibited the binding of EGF to A431 cells, indicating it to have transforming growth factor (TGF)-alpha activity. The extract contained appreciable amounts of immunoreactive PTH-related protein (PTH-rP) but negligible amounts of immunoreactive PTH. Thus, the PTH-like activity for stimulating cAMP generation in the bone and kidney was attributed to PTH-rP. Chromatographic analyses on reverse phase high performance liquid chromatography (HPLC) separated the PTH-rP activity from that of TGF-alpha and the bone resorbing activity in vitro was found only in the fractions of PTH-rP. It was concluded that this breast cancer produced PTH-rP as well as TGF-alpha, and the former was thought to have a major role to play in the humoral hypercalcemia of malignancy observed in this patient.
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PMID:Parathyroid hormone-related protein and transforming growth factor activities in an extract from a breast cancer associated with humoral hypercalcemia of malignancy. 255 42

The distribution and molecular characteristics of parathyroid hormone-related protein (PTH-rP) in conditioned media and cell extracts of cultured human keratinocytes, and in media from a variety of both normal and transformed epithelial and non-epithelial cell cultures were studied. PTH-rP of Mr 20,000 was observed in keratinocyte-conditioned media, and a larger form, Mr 29,000, in the keratinocyte cell extract. PTH-like bioactivity was also detected in media from 12 out of 17 epithelial cell cultures, but was not present in media from 14 cell cultures of non-epithelial origin. The molecular size of the PTH-like protein present in the epithelial cell media was approximately 20,000, corresponding with the PTH-rP in keratinocyte-conditioned medium. These observations may explain why hypercalcaemia is most commonly associated with tumours of epithelial origin.
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PMID:Parathyroid hormone-related proteins in cultured epithelial cells. 260 57

The hypercalcemia caused by malignancy factor, also called parathyroid hormone-related protein (PTHrP), exhibits most of the biological activities of parathyroid hormone (PTH) in kidney and bone. On the basis of the well-documented vascular action of PTH, we characterized the vasodilator action of human (h) PTHrP-(1-34) on a preparation of the isolated rat kidney, and its activity to stimulate adenylate cyclase in microvessels isolated from rabbit kidney cortex. Injection of sequential cumulative doses of hPTHrP-(1-34) into the isolated kidney preparation produced increasing vasodilatation up to 10(-8) M (EC50 of 3 x 10(-9) M) and decreasing responses thereafter. The maximal effect represented 26% of the reference relaxation induced by papaverine. Single injections of hPTHrP-(1-34) resulted in a greater (over 60%) vasodilatation. These results were reminiscent of the tachyphylaxis that occurs after repeated exposure to the peptide. The (3-34) PTH antagonist inhibited the hPTHrP-induced vasodilatation. Human PTHrP-(1-34) was equipotent with hPTH-(1-34) (EC50 values of 3 x 10(-9) M) but 5-fold less potent than rat (r) PTH-(1-34) in stimulating microvessel adenylate cyclase. GTP enhanced the enzyme responses to the peptides but reduced their potency. Both (3-34) and (7-34) PTH antagonists were inhibitors of hPTHrP- or PTH-stimulated microvascular adenylate cyclase. Synthetic hPTHrP-(1-16) had neither vasodilator nor adenylate cyclase-stimulating activity. This hPTHrP fragment exhibited some inhibitory effect on the hPTHrP-(1-34)-induced stimulation of microvessel adenylate cyclase. These results indicate that hPTHrP possesses PTH-like activity to cause vasorelaxation and to stimulate microvascular adenylate cyclase in the kidney.
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PMID:Renal vasodilatation and microvessel adenylate cyclase stimulation by synthetic parathyroid hormone-like protein fragments. 263 Feb 97

Hypercalcemia is one of well-recognized paraneoplastic syndromes and occurs occasionally in patients with oral cancers. Because bone is the richest source of calcium in the body, it has been proposed that humoral bone resorbing factors which are released by tumors are responsible for the pathogenesis of hypercalcemia. In the present study, partial purification and identification of bone resorbing humoral factors were carried out employing VX2 squamous cell carcinoma which has been known to induce hypercalcemia in rabbits. In addition, extra- and intra-cellular mechanisms which are operating to confer autonomous growth on VX2 cancer cells were also studied. VX2 carcinoma induced marked hypercalcemia not only in rabbits but also in nude mice in parallel with tumor enlargement. Administration of indomethacin (INDO), a prostaglandin (PG) synthesis inhibitor, before onset of the hypercalcemia prevented an elevation of serum calcium levels and growth of the tumor. INDO, however, failed to decrease serum calcium levels and tumor growth when administered after development of the hypercalcemia and tumor enlargement. These results indicate that not only PGs but other humoral factors are involved in the pathogenesis of the hypercalcemia seen in VX2 cancer-bearing animals. VX2 cancer cells in culture retained their cancerous phenotypic properties, synthesized PGE2, PGF2 alpha and 6-keto PGF1 alpha and secreted highly levels of PGE2, a powerful bone resorber, into the culture medium in a time- and cell density-dependent manner. The culture supernatants also contained a trypsin- and heat-sensitive bone risorbing factor (BRF) with a molecular weight of approximately 20kD. BRF was presumed to be similar to parathyroid hormone related protein (PTHrP) from its biological and biochemical behaviors. Both PGE2 and PTHrP promoted VX2 cell growth, thus suggesting that these two substances are autocrine growth factors for VX2 cells. Calcium stimulated VX2 cell growth and secretion of PGE2 and BRF (PTHrP) in a concentration-dependent fashion. Stimulation of VX2 cell proliferation by PGE2 and PTHrP was closely correlated with a transient elevation of intracellular free calcium ion ([Ca2+]i). [Ca2+]i elevated transiently in response to PGE2 and PTHrP was shown to be supplied by influx of extracellular free calcium ion ([Ca2+]e) through calcium channel present in plasma membrane. Involvement of protein kinase C in autocrine growth stimulation of VX2 cells by PGE2 and PTHrP was unclear. These results demonstrate that PGE2 and PTHrP secreted by VX2 cancer cells not only induce hypercalcemia but promote VX2 cell growth as autocrine growth factors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Mechanism of hypercalcemia associated with malignancy: interactions between induction of hypercalcemia and autonomous growth in VX2 cancer cells]. 263 47

Primary hyperparathyroidism is a common disorder and one that can usually (approximately 95%) be successfully treated by parathyroidectomy. PTH assays have become quite accurate for confirming the diagnosis. In patients with malignancy-associated hypercalcemia, parathyroid-like protein levels are usually increased, and radioimmunoassays being developed to quantitate serum levels of this protein will make the diagnosis easier. Treatment for a parathyroid adenoma is removal of the tumor and identification of the normal parathyroid glands. Treatment for primary or secondary hyperplasia is usually subtotal parathyroidectomy. Recurrent hyperparathyroidism is uncommon, except in patients with familial hyperparathyroidism, MEN-1 parathyroid carcinoma, or renal failure and secondary hyperparathyroidism. Persistent hyperparathyroidism is more common and is usually due to surgeon inexperience, but it is also caused by ectopically situated parathyroid glands, multiple abnormal parathyroid glands, or supranumerary parathyroid glands. Preoperative localization studies using ultrasound, thallium-technetium scanning, MRI, or CT scanning are reliable in patients with solitary parathyroid adenomas, but often fail to detect all of the abnormal parathyroid tissue in patients with multiple abnormal parathyroid glands. Intraoperative use of urinary cyclic AMP assays and rapid PTH assays have recently been used experimentally during parathyroid explorations to determine whether all hyperfunctioning parathyroid tissue has been removed, but these methods are not yet reliable or fast enough to be generally accepted. Most patients with primary hyperparathyroidism who are successfully treated by parathyroidectomy experience psychological, clinical, and metabolic benefits.
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PMID:Primary hyperparathyroidism. A surgical perspective. 267 68


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