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)

Lytic bone lesions and hypercalcemia are common features of multiple myeloma; however, they are exceptional in other B-cell malignancies. Myeloma bone involvement is related to an uncoupling process associating an increased osteoclastic resorption with decreased bone formation. Several osteoclast-activating factors such as interleukin-1 (IL-1), tumor necrosis factor, and interleukin-6 (IL-6) are involved in this process. IL-6, the major myeloma cell growth factor, could play a critical role in myeloma-induced bone resorption in association with other known or unknown hematopoietic growth factors, however.
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PMID:Mechanisms of bone lesions in multiple myeloma. 158 75

The human T-cell lymphotropic virus type I (HTLV-I) is capable of inducing a variety of host cellular genes including many of the cytokines responsible for immune regulation and osteoclast activation. This derangement in cytokine expression may contribute to the panoply of disease states associated with HTLV-I infection such as the adult T-cell leukemia (ATL) and HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). We wished to determine if there was a correlation between the expression of an array of cytokines and the diverse clinical manifestations of ATL and HAM/TSP. Utilizing the techniques of specific mRNA amplification by the polymerase chain reaction (PCR) as well as Northern blotting, we analyzed the ex vivo mRNA expression of gamma-interferon (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF-beta 1) in the peripheral blood of HAM/TSP and ATL patients as well as asymptomatic seropositive carriers. IFN-gamma, TNF-alpha, and IL-1 beta transcripts were up-regulated in patients with HAM/TSP and seropositive carriers when compared to their levels in ATL and normal controls. In contrast, the ATL patients constitutively expressed higher levels of TGF-beta 1 mRNA than HAM/TSP and seropositive carriers. In addition, TNF-alpha and IL-1 beta serum levels were elevated in HAM/TSP, but not in ATL patients nor seropositive carriers. However, the circulating leukemic cells from ATL patients secreted increased levels of TGF-beta 1 protein into the culture medium than T-cells derived from HAM/TSP patients. Collectively these results suggest that induction of IFN-gamma, TNF-alpha, and IL-1 beta in HAM/TSP may initiate an inflammatory cascade with subsequent events leading to immune mediated destruction of the central nervous system in these patients. Expression of osteoclast activators such as TNF-alpha and IL-1 beta is not associated with hypercalcemia in ATL. Finally, impaired cellular and humoral immune responses present in ATL, but not in HAM/TSP, may be related to elevated levels of TGF-beta 1 produced by the leukemic cells. These differences in retroviral-induced host cytokine expression in ATL and HAM/TSP suggest alternate roles in disease pathogenesis.
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PMID:Cytokine induction in HTLV-I associated myelopathy and adult T-cell leukemia: alternate molecular mechanisms underlying retroviral pathogenesis. 175 74

Recently, we have established a human squamous cell carcinoma of the maxilla (called MH-85) associated with hypercalcemia, leukocytosis, and cachexia in culture. MH-85 tumor cells caused the same paraneoplastic syndromes in tumor-bearing nude mice. We found that there was a sixfold increase in splenic size in MH-85 tumor-bearing mice. This increase paralleled tumor growth and was reversed by surgical removal of the tumor. Splenectomy in nude mice 1 wk before or 6 wk after tumor inoculation resulted in a decrease in tumor growth, and impairment of hypercalcemia, leukocytosis, and cachexia. In MH-85 tumor-bearing animals that had been pretreated by splenectomy, intravenous injection of fresh normal spleen cells caused an immediate reversal of leukocytosis, hypercalcemia, and cachexia. Since the presence of cachexia in both the patient and the mice carrying the tumor suggested tumor necrosis factor (TNF) may be overproduced, we injected polyclonal neutralizing antibodies raised against murine TNF into tumor-bearing mice. There was a rapid and reproducible decrease in blood ionized calcium, accompanied by suppression of osteoclast activity. No changes in blood ionized calcium were seen in mice injected with normal immune sera. In addition, there was an increase in body weight and decrease in white cell count. Plasma immunoreactive TNF was increased almost fourfold in tumor-bearing nude mice compared with control nude mice. Although TNF activity was undetectable in MH-85 culture supernatants, cells of the macrophage lineage, including spleen cells, released increased amounts of TNF when cultured with MH-85 tumor-conditioned media. These results suggest that splenic cytokines such as TNF may influence the development of the paraneoplastic syndromes of hypercalcemia, leukocytosis, and cachexia in these animals, as well as tumor growth. They also show that paraneoplastic syndromes may be due to factors produced by normal host cells stimulated by the presence of the tumor.
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PMID:Evidence that tumor necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcemia, and leukocytosis in a human tumor in nude mice. 199 5

Hypercalcemia occurs for various reasons in patients with malignant diseases. Most of these patients show a relative increase in bone resorption over bone formation. Increased renal tubular calcium reabsorption is also important for maintaining hypercalcemia in the majority of patients. Calcium absorption from the gut is usually decreased. In a few patients, fixed impairment of glomerular filtration contributes to hypercalcemia. Because the pathophysiology of hypercalcemia is heterogeneous, it may be considered as three separate syndromes: the humoral hypercalcemia of malignancy caused by systemic mediators; the hypercalcemia associated with localized osteolytic disease; and the hypercalcemia associated with myeloma and related hematologic malignancies. Increased bone resorption is a key feature in each of these syndromes. In malignant disease, bone resorption is enhanced because osteoclast activity is increased by the production of humoral mediators. These mediators are often produced by the tumor cells but are also produced by normal host cells that have been activated by the presence of the tumor. some of these mediators of hypercalcemia are systemic factors, but some act only locally. They include parathyroid hormone-related protein, transforming growth factor alpha, lymphotoxin, tumor necrosis factor, interleukin-1 alpha and 1,25-dihydroxyvitamin D.
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PMID:Incidence and pathophysiology of hypercalcemia. 210 29

It has long been known that complex interactions occur between tumors and normal host immune cells. The human melanoma cell line A375 has been used previously as an indicator cell for tumor cell cytotoxicity mediated by monocytes. During other studies on this tumor cell line, we noted that the conditioned media harvested from A375 cultures induced both the human monocytoid cell line U937 and human blood monocytes to release the cytokine tumor necrosis factor (TNF). We characterized this tumor factor which induced TNF release by monocytic cells. Purification was performed using ammonium sulfate precipitation, ion exchange (DEAE) chromatography, gel filtration, and reversed-phase high performance liquid chromatography. The factor copurified with granulocyte-macrophage colony-stimulating factor (GM-CSF). The purified material caused the release of TNF by U937 cells and stimulated formation of granulocyte-macrophage colonies in methyl cellulose. TNF release by U937 cells in response to A375-conditioned medium was inhibited by neutralizing antibodies to GM-CSF. The TNF-inducing activity in A375-conditioned medium was completely removed by an anti-GM-CSF affinity column. Western blotting using antibodies to GM-CSF confirmed a single Mr27,000 band in A375-conditioned medium. We found that recombinant human GM-CSF stimulated TNF production by the same cells as the tumor-conditioned medium. These data show that A375 human melanoma cells produce GM-CSF, which in turn causes TNF production by cells in the monocyte lineage. The combination of GM-CSF production by the tumor and TNF production by immune cells may influence not only tumor growth but also some of the paraneoplastic syndromes associated with malignancy such as hypercalcemia, cachexia and leukocytosis.
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PMID:Stimulation of tumor necrosis factor release from monocytic cells by the A375 human melanoma via granulocyte-macrophage colony-stimulating factor. 218 30

A parathyroid hormone-like peptide that probably causes hypercalcemia associated with solid tumors was recently characterized. It is a potent hypercalcemic and hypophosphatemic factor whose production is strongly associated with hypercalcemia and whose properties account for most aspects of the clinical syndrome. Diagnostic tests for this peptide have been developed. The parathyroid hormone-like peptide as well as other cytokines, such as tumor necrosis factor-alpha, likely play a role in causing hypercalcemia in multiple myeloma and lymphomas.
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PMID:Peptide mediators of hypercalcemia in malignancy. 218 36

During the past decade, specific mediators of bone destruction in hypercalcemia of malignancy have been identified and characterized. These humoral factors include parathyroid hormone-related protein, transforming growth factor alpha, and cytokines such as interleukin-1 and tumor necrosis factor. In metastatic hypercalcemia associated with breast cancer, prostaglandin secretion by tumor cells may be one of the important factors. Among the osteoclast activating factors associated with hypercalcemia in patients with myeloma, lymphotoxin plays a central but probably not exclusive role. Alterations of renal function in hematologic hypercalcemia may potentiate bone destruction that usually occurs in the presence of impaired rates of glomerular filtration. Further research is required to determine the relative contributions of bone and kidney to the pathogenesis of hypercalcemia of malignancy.
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PMID:Pathophysiology of cancer-associated hypercalcemia. 218 48

The endocrine abnormalities associated with acquired immunodeficiency syndrome (AIDS) are reviewed. These include adrenal insufficiency, hyporeninemic hypoaldosteronism, panhypopituitarism, hypogonadism, and alterations in thyroid function tests. AIDS-related infections or neoplasms may lead to hypercalcemia, whereas malabsorption may cause hypocalcemia. The possibility that AIDS-associated cachexia and hypertriglyceridemia may be caused by cachectin (tumor necrosis factor) is discussed, along with possible therapy for cachexia with megestrol acetate. Ketoconazole, sulfonamides, and pentamidine have specific, potentially deleterious metabolic effects when used in AIDS patients. Because treatment of endocrinological abnormalities of AIDS is often effective, improved diagnosis and appropriate therapy of these abnormalities will result in improved quality of life and, possibly, longer survival of patients with AIDS.
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PMID:Endocrinologic and metabolic manifestations of the acquired immunodeficiency syndrome. 224 1

We used a Chinese hamster ovary cell line that had been transfected with the human tumor necrosis factor (TNF) gene and constitutively produced TNF when transplanted in nude mice to study the effects of continuous production of TNF on calcium homeostasis. Continuous exposure to TNF caused increased osteoclastic bone resorption and humoral hypercalcemia in these animals. The mice bearing TNF-producing tumors were significantly hypercalcuric compared to mice bearing control tumors, but urinary cAMP excretion was unchanged. Mice bearing Chinese hamster ovary cell tumors containing the empty vector did not demonstrate hypercalcemia or increased bone resorption. This model system using transfected cells to continuously produce cytokines in vivo is more analogous to the pathophysiological conditions present in patients than intermittent injections and can produce much longer exposures than infusion pumps. Such model systems should allow a better understanding of the role of factors involved in humoral hypercalcemia.
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PMID:Tumors producing human tumor necrosis factor induced hypercalcemia and osteoclastic bone resorption in nude mice. 291 19

Myeloma cells destroy bone by producing an osteoclast-stimulating factor that has chemical and biological characteristics similar to the bone-resorbing activity present in the supernatants of activated leukocyte cultures. Recently, a number of bone-resorbing leukocyte cytokines have been identified, including interleukin-1, lymphotoxin, and tumor necrosis factor. We have examined the products of human myeloma cells for the presence of these bone-resorbing cytokines. In a tumor cell line derived from a patient who had myeloma with osteolytic bone lesions and hypercalcemia, we found that the myeloma cells induced bone-resorbing activity and cytotoxic activity in vitro. Most of the bone-resorbing activity and all cytotoxic activity were suppressed by neutralizing antibodies to lymphotoxin. The myeloma cells expressed both lymphotoxin and tumor necrosis factor mRNA, but no tumor necrosis factor could be detected in the cell-culture medium. Interleukin-1 mRNA was not detected in the myeloma cells, and biologic activity of interleukin-1 was not measurable in the medium harvested from the cultured cells. The bone-resorbing activity induced by recombinant tumor necrosis factor and recombinant interleukin-1 was not affected by treatment with the lymphotoxin antibodies. When lymphotoxin was infused subcutaneously into normal mice (10 micrograms per day for three days), their plasma calcium levels increased. We also evaluated four established cell lines derived from three other patients with myeloma, and found a similar pattern of lymphotoxin expression in each. It appears that production of the bone-resorbing cytokine lymphotoxin is related to osteoclastic bone destruction and hypercalcemia in patients with myeloma.
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PMID:Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells. 349 47


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