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 complication of lung and certain other cancers. The hypercalcemia results from the actions of tumor factors on bone and kidney. We report here the isolation of full-length complementary DNA clones of a putative hypercalcemia factor, and the expression from the cloned DNA of the active protein in mammalian cells. The clones encode a prepro peptide of 36 amino acids and a mature protein of 141 amino acids that has significant homology with parathyroid hormone in the amino-terminal region. This previously unrecognized hormone may be important in normal as well as abnormal calcium metabolism.
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PMID:A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. 361 18

An appreciation of the pathogenesis of the hypercalcemia of malignancy is essential to its management. At the outset, since most patients with symptomatic hypercalcemia of malignancy are dehydrated, infusion of 2 to 3 liters of saline per day will at least partially reduce serum calcium levels. Induction of calciuresis by infusing larger volumes of saline simultaneously with parenteral administration of furosemide may reduce the serum calcium concentration to normal in the short term. Of major importance in long-term therapy, however, are drugs that inhibit bone resorption, a major cause of hypercalcemia. These include calcitonin, plicamycin, glucocorticoids, prostaglandin synthetase inhibitors, and the diphosphonates. These agents may provide long-term control of hypercalcemia in many patients. Reduction of intestinal calcium absorption by dietary means or by glucocorticoid therapy is often effective in the rare subset of patients with increased serum levels of 1,25-dihydroxyvitamin D. Oral and intravenous phosphorus therapy may be effective via unknown mechanisms in some patients. The diphosphonates, in particular, should greatly facilitate management of both acute and chronic hypercalcemia of malignancy. Daily intravenous infusion of etidronate disodium (etidronate) with saline over a period of three to six days, for example, appears to be a safe and effective means of restoring serum calcium concentrations to the normal range. Study results have shown that more than 90 percent of patients have a response to etidronate. Oral administration of the drug has been demonstrated to maintain normal serum calcium concentrations.
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PMID:Therapy of hypercalcemia of malignancy. 382 96

A 42-year-old woman, with a previously resected jejunal leiomyoblastoma, was first seen with liver metastases 31/2 years after the tumor resection. Intractable malignant hypercalcemia appeared eight months later, together with renal insufficiency. No osteolytic lesions were detected. Levels of parathyroid hormone, cyclic adenosine monophosphate, and 1,25-dihydroxycholecalciferol (1,25[OH]2D) were not useful in distinguishing between the hypercalcemia of malignancy and concurrent hyperparathyroidism. Despite renal insufficiency, hypercalcemia, and subtotal parathyroidectomy, the 1,25(OH)2D levels remained elevated, consistent with the speculation that a tumor product stimulated 1-alpha-hydroxylation of 25-hydroxycholecalciferol. Phenytoin and phenobarbital (enzyme induction therapy), in combination with phosphorus and glucocorticoids, appeared to be useful in controlling the hypercalcemia.
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PMID:Leiomyoblastoma associated with intractable hypercalcemia and elevated 1,25-dihydroxycholecalciferol levels. Treatment by hepatic enzyme induction. 383 34

Tumor-derived transforming growth factors (TGF) have been proposed as possible mediators of hypercalcemia in malignancy. We have studied the action of recombinant human TGF-alpha in cultured bone cells and in bone explant cultures. In clonal UMR-106 rat osteosarcoma cells, TGF-alpha and epidermal growth factor (EGF) were equipotent in binding to the EGF receptor. TGF-alpha and EGF both stimulated resorption of neonatal mouse calvaria, and maximal responses were obtained with 10 ng/ml of TGF-alpha after 72 h in culture. The effects of both TGF-alpha and EGF in calvaria, but not those of parathyroid hormone, were inhibited by 5 X 10(-7) M indomethacin. Fetal rat limb bone cultures were less sensitive to TGF-alpha than neonatal mouse calvaria, with a concentration of 30 ng/ml being required to stimulate resorption in this system. The bone-resorbing activity of TGF-alpha in fetal rat bones was inhibited by 10 ng/ml calcitonin but not by 5 X 10(-7) M indomethacin. EGF at concentrations up to 300 ng/ml did not stimulate resorption of the limb bones at time periods up to 66 h. The results indicate that human TGF-alpha is a potent bone-resorbing agent, and support the concept that this growth factor exhibits some effects distinct from those of EGF. TGF-alpha could play an etiologic role in the hypercalcemia of malignancy.
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PMID:Human transforming growth factor-alpha stimulates bone resorption in vitro. 387 79

The relative efficacy of five drugs in the treatment of hypercalcemia of malignancy was assessed in a randomized study. The drugs were oral phosphate, mithramycin, glucocorticoids, indomethacin, and ethane-1-hydroxy-1, 1-diphosphonate (EHDP). No single agent was universally effective. Oral phosphate and mithramycin were the most efficacious, each producing a decrease in serum calcium concentrations in four of five patients, although there were serious disadvantages with the use of each. Glucocorticoids were effective in only two of five patients who received randomized treatment. A further five patients received nonrandomized treatment with glucocorticoids, and only three of these showed response. Indomethacin was effective in only one of five patients to whom it was given, and EHDP was effective also in only one of five patients. The new diphosphonate, 3-amino-1-hydroxypropane-1, 1-diphosphonate (APD) was evaluated in the treatment of hypercalcemia in 13 patients with malignant disease and two with primary hyperparathyroidism. APD caused a significant decrease in serum calcium concentration in nine of 12 patients within 72 hours. These results indicate that there is no currently available pharmacologic agent that is entirely satisfactory in the treatment of hypercalcemia. The most effective agents were mithramycin, oral phosphate, and APD. Glucocorticoids and orally administered EHDP showed limited effectiveness, and indomethacin was ineffective in the majority of patients.
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PMID:Comparative study of available medical therapy for hypercalcemia of malignancy. 621 78

A women with hypercalcemia and a hypernephroma confined to the left kidney underwent nephrectomy and subsequent resolution of hypercalcemia. Serum parathyroid hormone was undetectable in peripheral blood as well as in the left renal vein at surgery. Parathyroid hormone was also undetectable in the tumor extract using three different antisera to parathyroid hormone. Measurement of plasma prostaglandin E and 13, 14-dihydro-15-keto-prostaglandin E2 revealed levels within the normal range. The serum 1,25-dihydroxyvitamin D concentration was below normal and nephrogenous cyclic adenosine monophosphate was markedly elevated. The humoral agent responsible for hypercalcemia in this patient was not identified. This case emphasizes the need to search for new hypercalcemic factors in patients with hypercalcemia of malignancy.
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PMID:Humoral hypercalcemia of malignancy: a syndrome in search of a hormone. 629 89

A radioreceptor assay for serum 1,25-dihydroxyvitamin D (calcitriol) was used to screen patients with hypercalcemia of malignancy. Three patients with non-Hodgkin's lymphoma and hypercalcemia (serum Ca, 12.0, 13.4, and 13.0 mg/dL, respectively) had increased serum calcitriol levels (56, 72, and 77 pg/mL, respectively; normal, less than 50 pg/mL). Elevated levels of calcitriol, an active vitamin D metabolite, occurred in the presence of significant renal impairment (creatinine clearance, 8 to 19 mL/min) and relative parathyroid suppression (serum immunoreactive parathyroid hormone, 17 to 39 microL-eq/mL; mean value in end-stage renal disease, 182 +/- 39 microL-eq/mL). Hypercalcemia and excessive serum calcitriol levels responded to glucocorticosteroid therapy. In two patients, the hypercalcemia and increased serum calcitriol level were related to a tumor, but not to the serum immunoreactive parathyroid hormone level. Fractional intestinal 47Ca absorption, measured in one patient, was increased (0.94; normal, less than 0.61) and varied directly with the serum calcitriol level. No patient had evidence of sarcoidosis. Hypercalcemia associated with certain lymphomas may be caused by the increased synthesis of calcitriol by lymphoma cells.
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PMID:Hypercalcemia associated with increased serum calcitriol levels in three patients with lymphoma. 654 27

Evidence is presented that a tumor-derived transforming growth factor is responsible for stimulating bone resorption and causing hypercalcemia in an animal tumor model of the hypercalcemia of malignancy. Both conditioned medium harvested from cultured tumor cells and tumor extracts of the transplantable rat Leydig cell tumor associated with hypercalcemia contained a macromolecular bone resorbing factor with the chemical characteristics of a tumor-derived transforming growth factor.
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PMID:Tumor-derived growth factor increases bone resorption in a tumor associated with humoral hypercalcemia of malignancy. 657 2

The number of agents and treatment regimens which can be used in the medical treatment of hypercalcemia has increased markedly over the last 5 yr. As this list has increased, clinicians are anxious to know more about the humoral and cellular mechanisms which are responsible for the hypercalcemia of malignancy and to understand how these drugs work. Unfortunately there is no treatment available presently which is uniformally safe and effective, and the potential pathogenetic mechanisms responsible for hypercalcemia are hotly debated. In this review, we plan to summarize current views of the pathogenesis, clinical features and treatment of hypercalcemia associated with malignant disease.
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PMID:The hypercalcemia of malignancy: pathogenesis and management. 675 68

Hypercalcemia is a common and serious complication of neoplastic disease. It may occur in association with a variety of tumors and usually indicates a lack of tumor control. Early symptoms are nonspecific, involving several organ systems in a syndrome that may progress rapidly to death. The pathophysiology of hypercalcemia is complex and not fully understood. Research continues on local mechanisms of bone destruction at sites of bone metastases and the identification of humoral tumor-derived osteolytic factors. The therapeutic approach to hypercalcemia should be sequential, dictated more by clinical symptoms than by absolute calcium levels. The diversity of measures and agents used in the therapy of hypercalcemia of malignancy reflects the multiple mechanisms involved. The therapeutic maneuvers outlined usually yield temporary success and must be accompanied by specific antitumor therapy, the ultimate treatment for the hypercalcemia of neoplastic disease.
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PMID:Hypercalcemia in malignant disease. 676 Sep 66


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