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)

We reported first in this study that human thyroid cell line NIM 1 established from a patient with papillary adenocarcinoma of the thyroid associated with hypercalcemia and peripheral neutrocytosis produced interleukin (IL)-1 alpha and IL-1 beta in the culture supernatant and cell lysate as detected by murine thymocyte proliferative response and enzyme-linked immunosorbent assay. Production of IL-1 alpha and IL-1 beta was further confirmed by the demonstration of IL-1 alpha and IL-1 beta messenger ribonucleic acid expression with Northern blot hybridization analysis. The in vitro growth of NIM 1 cells was inhibited by the addition of anti-IL-1 alpha and IL-1 beta antibody. The growth of NIM 1 cells was further enhanced by the addition of recombinant human IL-1 alpha and IL-1 beta, whereas this enhancement was also inhibited by the addition of anti-IL-1 antibody. IL-1 receptors were expressed on NIM 1 cells. These results suggest that IL-1 plays a regulatory role in the growth of NIM 1 cells by an autocrine mechanism.
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PMID:Autocrine stimulation of interleukin-1 in the growth of human thyroid carcinoma cell line NIM 1. 842 Oct 76

Cachexia consists of a constellation of metabolic changes that occur in cancer patients, including the reduction of muscle and fat tissue, asthenia, anorexia, hypoglycemia and hypercalcemia. These syndromes complicate therapeutic intervention and decrease the quality of life of the patient. This review discusses the involvement of cytokines in cancer cachexia and describes the contribution of IL-6 and other cytokines to the wasting of C-26-bearing mice. The neutralization of IL-6 by antibody, or IL-6 receptor antagonism by suramin, significantly reduce the severity of key parameters of cachexia. The participation of several other factors (PGE2, IL-1, IL-10 and TNF-alpha) in the cellular communication between the C-26 tumor cell and tumor-infiltrating macrophages is also described.
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PMID:Inhibition of experimental cancer cachexia by anti-cytokine and anti-cytokine-receptor therapy. 938 67

Circulating parathyroid hormone-related protein (PTHrP) is the primary humoral factor in dogs with spontaneous humoral hypercalcemia of malignancy (HHM) and adenocarcinomas derived from apocrine glands of the anal sac. A canine apocrine adenocarcinoma model of HHM in nude mice (CAC-8) was developed and characterized. After 32 passages in vivo, a spontaneous variant of the tumor (CAC-8 Lo Ca) that has altered cellular morphology and that fails to induce HHM in tumor-bearing nude mice has been discovered. The hypercalcemic and nonhypercalcemic tumor lines were compared by tumor weight, effect on body weight, serum calcium concentration, plasma PTHrP concentration, histopathology, expression of PTHrP protein by radioimmunoassay and immunohistochemistry, and expression of PTHrP mRNA by in situ hybridization and northern blot analysis. Messenger RNA expression for other factors and cytokines known to alter PTHrP secretion or bone resorption in vivo, including tumor necrosis factor alpha (TNF alpha), interleukin (IL)-1, IL-6, and transforming growth factor beta (TGF beta), were also measured in the adenocarcinomas. There was no significant difference in weight of individual tumors. Nude mice bearing the CAC-8 (Lo Ca) tumor maintained normal body weight as compared with non-tumor-bearing control mice. In contrast, mice with the CAC-8 (Hi Ca) tumor had markedly decreased body weights. The CAC-8 (Hi Ca) tumor-bearing mice had severe hypercalcemia (mean = 13.4 mg/dl) and increased plasma concentrations of PTHrP (30.4 pM), whereas the CAC-8 (Lo Ca) tumor-bearing mice had a mean serum calcium concentration of 10.1 mg/dl and mildly increased PTHrP concentrations (5.7 pM) as compared with control mice (9.0 mg/dl and 1.0 pM, respectively). The original tumor (CAC-8 [Hi Ca]) is a well-differentiated adenocarcinoma, whereas the variant tumor (CAC-8 [Lo Ca]) is a solid carcinoma with both polygonal and spindle-shaped cells. The CAC-8 (Lo Ca) tumor had decreased PTHrP mRNA expression and protein synthesis. Messenger RNA expression of TGF beta, TNF alpha, IL-1, and IL-6 was similar in both tumors and was consistent with the central role of PTHrP in the induction of hypercalcemia in this animal model.
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PMID:Dependence of humoral hypercalcemia of malignancy on parathyroid hormone-related protein expression in the canine anal sac apocrine gland adenocarcinoma (CAC-8) nude mouse model. 975 39

Lung cancer is commonly associated with multiorgan metastasis, and bone is a frequent metastatic site for lung cancer. Nevertheless, no bone metastasis model of lung cancer with multiorgan dissemination is available, which could provide opportunity to study the molecular pathogenesis. We examined the abilities of eight human lung cancer cell lines injected intravenously into natural killer (NK) cell-depleted SCID mice to generate metastatic nodules in bone and multiple organs, and explored the correlation of the parathyroid hormone-related protein (PTHrP) with the bone metastasis. Although all the small-cell carcinoma cell lines (SBC-5, SBC-3, SBC-3/ADM, H69, H69/VP) formed metastatic nodules in multiple organs (liver, kidney, and lymph nodes), only SBC-5 cells reproducibly developed bone metastases. Squamous cell carcinoma (RERF-LC-AI) cells metastasized mainly into the liver and kidneys, whereas adenocarcinoma (PC-14, A549) mainly produced colonies in the lungs. As assessed by X-ray photography, the osteolytic bone metastases produced by SBC-5 cells were detected as early as on day 28, and all recipient mice developed bone metastasis by day 35. The expression of PTHrP in eight cell lines was directly correlated with the formation of bone metastasis. No correlation was observed between the formation of bone metastasis and the expression of other metastasis-related cytokines (IL-1, IL-6, IL-8, IL-10, IL-11, TNF-alpha, VEGF, M-CSF). Consistent with the formation of bone metastasis by SBC-5 cells, the levels of PTHrP and calcium in the mouse serum were increased in a time-dependent manner, suggesting that PTHrP produced by human lung cancer may play a crucial role in the formation of bone metastasis and hypercalcemia. These findings indicate that a bone metastasis model of SBC-5 cells may be useful for clarifying the molecular aspects of the metastatic processes in different organ microenvironments and the development of therapeutic modalities for lung cancer patients with bone metastases.
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PMID:Bone metastasis model with multiorgan dissemination of human small-cell lung cancer (SBC-5) cells in natural killer cell-depleted SCID mice. 1141 46

A 64-year-old woman with adult T cell leukemia (ATL) was admitted to our hospital with severe hypercalcemia. The serum calcium level was elevated to 14.9 mg/dl. Biochemical parameters for bone formation including serum osteocalcin (bone Gla protein, BGP) and alkaline phosphatase (ALP) were normal. The serum levels of tartrate-resistant acid phosphatase (TRAP), a parameter for bone resorption, were increased (4.6 KAU). The serum level of parathyroid hormone-related protein (PTHrP) was elevated (343 pmol/l). The cytokines with stimulatory effects on bone resorption, such as interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor-alpha, were not detected. Serum Ca levels, PTHrP levels, and TRAP levels decreased with the decrease in ATL cells after chemotherapy, while serum BGP levels and ALP levels increased. On the 29th hospital day, ATL cells began to increase again. Then serum PTHrP levels, Ca levels, and TRAP levels increased, while serum BGP levels and ALP levels decreased. A marked excessive bone resorption with suppressed bone formation (uncoupling) occurred in this patient. The ATL cells produced not only PTHrP but also IL-1alpha and IL-1beta. These results suggest that PTHrP may act as a humoral factor and IL-1 may act as a local factor in bone metabolism of ATL patients.
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PMID:Bone resorption associated with uncoupling of osteoclastic and osteoblastic activities in adult T cell leukemia with hypercalcemia: case report. 1152 70

Hypercalcemia is one of the most frequent and serious complications in patients with adult T-cell leukemia (ATL) and is due to marked bone resorption by accumulation of osteoclasts (OCLs). Although several cytokines such as interleukin 1 and parathyroid hormone-related protein are thought to be involved in the development of high serum Ca(++) levels, its precise underlying mechanism remains unknown. This study analyzed the expression of various genes that are thought to regulate serum Ca(++) levels in ATL and showed that the overexpression of the receptor activator of nuclear factor kappaB (RANK) ligand gene correlated with hypercalcemia. ATL cells from patients with hypercalcemia, which highly expressed the transcripts of the RANK ligand (RANKL) gene, induced the differentiation of human hematopoietic precursor cells (HPCs) into OCLs in vitro in the presence of macrophage colony-stimulating factor (M-CSF). In contrast, ATL cells from patients without hypercalcemia did not induce such differentiation, suggesting that the induction of the differentiation correlated with the expression of the RANKL gene in ATL cells. Cell differentiation was suppressed by osteoprotegerin/Fc, an inhibitor of RANKL, indicating that such differentiation occurred through the RANK-RANKL pathway. In addition, direct contact between ATL cells and HPCs was essential for the differentiation, suggesting that not the soluble form but membrane-bound RANKL played a role in this process. These results strongly suggested that ATL cells induce the differentiation of HPCs to OCLs through RANKL expressed on their surface, in cooperation with M-CSF, and ultimately cause hypercalcemia.
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PMID:Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear factor kappaB ligand on adult T-cell leukemia cells. 1178 Dec 48

Insufficient dietary magnesium (Mg) intake has been associated in humans with low bone mass. Mg deficiency in the rat has suggested bone loss is due to increased bone resorption and/or inadequate bone formation during remodeling. The purpose of this study was to assess the effect of a low Mg diet on bone and mineral metabolism in the young and mature BALB/c mouse and explore the hypothesis that inflammatory cytokines may contribute to Mg deficiency-induced osteoporosis. Using an artificial diet, we induced targeted Mg depletion (0.002% Mg) with all other nutrients maintained at the normal level. In all Mg-depleted mice, hypomagnesemia developed and skeletal Mg content fell significantly. The serum Ca in Mg-deficient mice was higher than in control mice; however, serum PTH levels were not significantly different. Osteoprotegerin (OPG) in dosages that inhibit osteoclastic bone resorption did not prevent hypercalcemia in Mg-deficient animals. No significant difference in serum Ca was observed between groups when dietary Ca was reduced by 50%, suggesting that a compensatory increase in intestinal absorption might account for the hypercalcemia. Growth plate width decreased 33% in young Mg-deficient animals and chondrocyte columns decreased in number and length, suggesting that Mg deficiency reduced bone growth. Trabecular bone volume in the metaphysis of the tibia in these animals was decreased and osteoclast number was increased by 135%. Osteoblast number was significantly reduced. Immunohistochemistry revealed that substance P increased 230% and 200% in megakaryocytes and lymphocytes, respectively, after 1 day of Mg depletion. IL-1 increased by 140% in osteoclasts by day 3 and TNF alpha increased in osteoclasts by 120% and 500% in megakaryocytes on day 12. This study demonstrates a profound effect of Mg depletion on bone characterized by impaired bone growth, decreased osteoblast number, increased osteoclast number in young animals, and loss of trabecular bone with stimulation of cytokine activity in bone.
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PMID:Magnesium deficiency: effect on bone and mineral metabolism in the mouse. 1237 Jul 96

Bisphosphonates are endogenous pyrophosphate analogs in which a carbon atom replaces the central atom of oxygen. They are indicated in non-neoplastic diseases including osteoporosis, corticosteroid-induced bone loss, Paget disease, and in cancer-related diseases such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer. There is now extensive in vitro evidence suggesting a direct antitumor effect of bisphosphonates at different levels of action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on tumor cells, and the effects on the regulation of cell growth, apoptosis, angiogenesis, cell adhesion, and invasion, with particular attention to biological properties. Well designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates may be clinically relevant. On the basis of their effects on macrophages, we may divide bisphosphonates into two distinct categories: aminobisphosphonates, which sensitize macrophages to an inflammatory stimulus inducing an acute-phase response, and non-aminobisphosphonates that can be metabolized into macrophages and that may inhibit the inflammatory response of macrophages. There is evidence of aminobisphosphonate-induced pro-inflammatory response, in particular, related to modifications of the cytokine network. Several in vivo studies have demonstrated an acute-phase reaction after the first administration of aminobisphosphonates, with a significant increase in the main pro-inflammatory cytokines. However, a peculiar aspect concerning the action of non-aminobisphosphonates seems to be an anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from activated macrophages, such as interleukin (IL)-6, tumor necrosis factor-alpha and IL-1. The inhibition of inflammatory responses is demonstrated in both in vivo and in vitro models. This activity suggests the use of non-aminobisphosphonates in several inflammatory diseases characterized by macrophage-mediated production of acute-phase cytokines, as prevention of erosions in rheumatoid arthritis, and of loosening of joint prostheses, as well as possibly in osteoarthritis, ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy.
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PMID:Bisphosphonate effects in cancer and inflammatory diseases: in vitro and in vivo modulation of cytokine activities. 1524 2

There is considerable evidence that osteoclasts are involved in the pathogenesis of juxta-articular bone destruction in rheumatoid arthritis. Vacuolar ATPases (V-ATPases), which are highly expressed in the ruffled border membrane of osteoclasts, play a central role in the process of bone resorption, and V-ATPase inhibitors are effective in preventing bone destruction in several animal models of lytic bone diseases. Here, we evaluated for the first time the effects of V-ATPase inhibition in rats with adjuvant-induced arthritis (AIA) using FR177995, a novel V-ATPase inhibitor. FR177995 completely inhibited H(+) transport driven by V-ATPase, but exerted no effect on the H(+) transport activities of F- and P-ATPase, indicating that FR177995 is a specific inhibitor of V-ATPase. FR177995 acted directly on osteoclastic bone resorption and equally inhibited in vitro bone resorption stimulated by IL-1, IL-6 or PTH. In addition, FR177995 dose-dependently reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats. When FR177995 was administered to AIA rats once a day, the loss of femoral bone mineral density was significantly improved. Moreover, indicators of cartilage damage (arthritis score and glycosaminoglycan content in the femoral condyles) and inflammation parameters (paw swelling volume, erythrocyte sedimentation rate and plasma sialic acid level) were found to be unexpectedly ameliorated. These results strongly suggest that V-ATPase may be an interesting drug target in the treatment of rheumatoid arthritis.
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PMID:FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats. 1715 74

Cytokines have not been employed in clinical laboratory tests because of the many biological activities of individual cytokines and too complicated cytokine network. However, abnormal laboratory data and symptoms can be interpreted by blood cytokine levels. [Cytokines attributable to abnormal data and symptoms] For example, cytokines attributable to abnormal data and symptoms in rheumatoid arthritis are as follows: joint pain: TNFalpha, IL-1, IL-6, and IL-18; general fatigue and appetite loss: TNFalpha and IL-1; leukocytosis: G-CSF produced by IL-1-stimulated macrophages etc; thrombocytosis: megakaryocyte potentiating activity of IL-6; anemia: hepcidin up-regulated by IL-6, which inhibits iron absorption from the intestine, and IL-1, which decreases the blood iron level and promotes ferritin synthesis. [Differential diagnosis using blood cytokine levels] Blood cytokine levels are useful and important in the differential diagnosis of inflammatory disorders such as neutrophilia, eosinophilia, and especially in distinguishing tumoral fever from infectious fever in malignant lymphomas. [Disease/disorder-specific cytokines] In recent years, disease- or disorder specific cytokines have been identified, making cytokines more important in clinical use. For example, IL-18 for adult-onset Still disease; IFNgamma for hemophagocytic syndrome; IL-5 for allergic disorders; thrombopoietin for immune thrombocytopenic purpura; vascular endothelial growth factor for POEMS syndrome; PTH-rP for malignancy associated hypercalcemia. [Flow cytometric measurement of cytokines] Recently, a flow cytometric method has been developed in addition to ELISA. With this method, 30 cytokine concentrations can be measured simultaneously within four hours with a wide range of detection limit and high cost performance. Cytokines will be included in laboratory tests with this method.
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PMID:[Blood cytokine levels as a clinical laboratory test]. 1744 72


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