Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating N-terminal PTH-related protein (PTHrP), N-terminal PTH, and 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations were measured in normal dogs and dogs with cancer-associated hypercalcemia (CAH), parathyroid adenomas, and miscellaneous tumors. PTHrP was undetectable (less than 1.8 pM) in normal dogs and increased in dogs with CAH due to adenocarcinomas derived from apocrine glands of the anal sac (44.9 +/- 27 pM), lymphoma (8.3 +/- 4.4 pM), and miscellaneous carcinomas (13.3 +/- 11.4 pM). The PTHrP concentration decreased in dogs with lymphoma and anal sac adenocarcinomas after successful treatment of CAH. The PTHrP concentration had a significant linear correlation with total serum calcium in dogs with anal sac adenocarcinomas and hypercalcemia, but not in dogs with lymphoma and hypercalcemia. Serum N-terminal PTH concentrations were usually in the normal range (12-34 pg/ml) for all groups of dogs except dogs with parathyroid adenomas (83 +/- 38 pg/ml). The serum PTH concentration increased after successful treatment of CAH. Serum 1,25-(OH)2D concentrations were decreased, normal, or increased in dogs with CAH, and 1,25-(OH)2D levels decreased after treatment of CAH. In summary, circulating concentrations of PTHrP are consistently increased in dogs with CAH, and PTHrP appears to play an important role in the induction of hypercalcemia.
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PMID:Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia. 150 57

Tumors from patients with humoral hypercalcemia of cancer produce a parathyroid hormone-related protein (PTHRP). We have developed two region-specific immunoassays capable of measuring PTHRP in plasma: an immunoradiometric assay directed toward PTHRP amino acid sequence 1 to 74 and a radioimmunoassay directed toward PTHRP amino acid sequence 109 to 138. Sixty normal subjects had low or undetectable plasma PTHRP (1 to 74) concentrations (mean, 1.9 pmol per liter) and undetectable PTHRP (109 to 138) concentrations (less than 2.0 pmol per liter). Patients with humoral hypercalcemia of cancer (n = 30) had elevated levels of both PTHRP (1 to 74) (mean, 20.9 pmol per liter) and PTHRP (109 to 138) (mean, 23.9 pmol per liter). The plasma concentrations of immunoreactive PTHRP correlated with the levels of urinary cyclic AMP excreted; in some patients, the concentrations decreased after the tumors were resected. Patients with chronic renal failure (n = 15) had plasma PTHRP (1 to 74) concentrations similar to those in the normal subjects, but their plasma PTHRP (109 to 138) concentrations were elevated (mean, 29.6 pmol per liter). The levels of both peptides were normal in patients with hyperparathyroidism and those with hypercalcemia due to various other causes. Breast milk contained high concentrations of PTHRP. An anti-PTHRP (1 to 36) immunoaffinity column failed to extract PTHRP (109 to 138) immunoactivity from plasma, suggesting that the C-terminal region circulates as a separate peptide. We conclude that plasma PTHRP concentrations are high in the majority of patients with cancer-associated hypercalcemia and that the circulating forms of PTHRP in such patients include both a large N-terminal (1 to 74) peptide and a C-terminal (109 to 138) peptide. Measuring the concentrations of PTHRPs may be useful in the differential diagnosis of hypercalcemia.
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PMID:Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. 232 83

A canine adenocarcinoma model (CAC-8) of humoral hypercalcemia of malignancy was evaluated for transforming growth factors (TGF)-alpha and -beta, PTH-like activity [adenylate cyclase-stimulating activity (ACSA)], and in vitro bone-resorbing activity. Biological activities present in CAC-8 were separated by reverse phase or cation exchange HPLC. TGF alpha in tumor extract was separated from TGF beta and ACSA by reverse phase HPLC. TGF alpha eluted between 26-30% acetonitrile and was identified by RIA. After the initial reverse phase separation, TGF beta and ACSA in tumor extract coeluted between 36-38% acetonitrile. Sequential cation exchange followed by reverse phase HPLC separated TGF beta from ACSA. Evaluation of fractions containing ACSA using an in vitro bone-resorbing assay demonstrated copurification of ACSA and bone-resorbing activity. The PTH receptor antagonist [Nle8,18,Tyr34]bovine PTH-(3-34)-amide, but not [Nle8,18,Tyr34]bovine PTH-(7-34)-amide, completely inhibited ACSA in column eluates. Conditioned cell culture medium from CAC-8 primary cultures contained predominantly latent TGF beta that could be activated by acidification. These findings indicate that the CAC-8 model of cancer-associated hypercalcemia produces a PTH-like factor, TGF alpha, and TGF beta that were separable by reverse phase or cation exchange HPLC. This feature should be useful to investigate the role of TGFs and PTH-like proteins in the pathogenesis of humoral hypercalcemia of malignancy.
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PMID:Separation of parathyroid hormone-like activity from transforming growth factor-alpha and -beta in the canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy. 253 81

Gallium is a group IIIa transition metal that lowers serum calcium by an unknown mechanism and has been utilized in the treatment of cancer-associated hypercalcemia. The purpose of this study was to histomorphometrically investigate the ultrastructural effects of gallium nitrate on osteoclasts and osteoblasts in trabecular bone of normal nude mice and nude mice with humoral hypercalcemia of malignancy. Two groups of normal nude mice (n = 7 and n = 8, respectively) and two groups of hypercalcemic nude mice (n = 9) bearing a serially transplantable canine adenocarcinoma (CAC-8) were treated with vehicle or gallium nitrate. Osteoclasts were hypertrophied in vehicle-treated tumor-bearing nude mice as compared with vehicle-treated nontumor-bearing nude mice. Osteoclasts from tumor-bearing nude mice treated with gallium nitrate were significantly decreased in size and had fewer intracytoplasmic vesicles as compared with osteoclasts from vehicle-treated tumor-bearing nude mice. Degenerate osteoclasts, characterized by pyknotic nuclei and increased cytoplasmic vacuolation, were observed in both groups of gallium-treated nude mice. Osteoblasts from vehicle-treated tumor-bearing nude mice were hypertrophied and had extensive lamellar arrays of rough endoplasmic reticulum as compared with osteoblasts from vehicle-treated nontumor-bearing nude mice. Osteoblasts in gallium-treated nude mice (tumor-bearing and nontumor-bearing) were small and flattened with poorly developed cytoplasmic organelles. This investigation demonstrated that osteoclasts and osteoblasts in nude mice treated with gallium nitrate had ultrastructural evidence of decreased metabolic and functional activity. The results suggest that gallium nitrate lowers serum calcium by inhibiting osteoclastic bone resorption.
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PMID:Ultrastructural and histomorphometric evaluations of gallium nitrate on bone in nude mice bearing a canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy. 772 96

Immunohistochemical and ultrastructural investigations of thyroid C cells were conducted in male nude (athymic) mice bearing a serially transplantable canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy following subcutaneous administration of gallium nitrate. The following four groups were investigated: 1) vehicle-treated non-tumor-bearing control mice; 2) non-tumor-bearing mice treated with gallium nitrate; 3) vehicle-treated hypercalcemic mice bearing CAC-8; and 4) CAC-8 tumor-bearing mice treated with gallium nitrate. Gallium nitrate-treated tumor-bearing mice had a significant decrease in serum calcium as compared with tumor-bearing controls. C cells of non-tumor-bearing mice stained intensely for calcitonin and calcitonin gene-related peptide and weakly for chromogranin A and neuron-specific enolase. In C cells of both vehicle- and gallium-treated tumor-bearing mice, immunoreactive staining was decreased for calcitonin, calcitonin gene-related peptide, and chromogranin A, whereas there was a moderate increase in staining for neuron-specific enolase. Ultrastructurally, thyroid C cells in hypercalcemic tumor-bearing control and gallium-treated mice were hypertrophic and markedly degranulated as compared with those of non-tumor-bearing controls. Hypertrophic C cells contained few mature secretory granules, a well-developed Golgi apparatus, and lamellar arrays of rough endoplasmic reticulum. There was no evidence of C-cell hyperplasia. Immunohistochemical and ultrastructural findings revealed that C cells in mice with cancer-associated hypercalcemia were primarily in the actively synthesizing phase of the secretory cycle and had diminished immunoreactivity for calcitonin, calcitonin gene-related peptide, and chromogranin A.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of humoral hypercalcemia of malignancy and gallium nitrate on thyroid C cells in nude mice: immunohistochemical and ultrastructural investigations. 805 30

Hypercalcaemia is the most common metabolic complication of malignant disease. It is an important cause of morbidity in cancer patients and is potentially amendable to treatment. Bone metastases are rarely the cause of hypercalcaemia in malignancy, the elevation in calcium concentrations usually resulting from the effects of humoral mediators released by the tumour. Many factors isolated from tumours have the potential to cause hypercalcaemia, but the most important is parathyroid hormone related protein (PTHrP), a peptide which mimics the effect of PTH. Treatment of cancer associated hypercalcaemia is based on an initial phase of volume repletion with isotonic saline, followed by drug treatment to inhibit bone resorption. Bisphosphonates are the most widely used agents in the treatment of such bone resorption, are very effective and have minimal toxicity. Gallium nitrate is also effective but less widely used. The combination of bisphosphonates and calcitonin has been found to be particularly useful in patients with severe hypercalcaemia, since this gives a more rapid reduction in serum calcium values than can be achieved with bisphosphonate alone. In the longer term, effective control of hypercalcaemia depends on treating the primary tumour. In the majority of cases this is not possible, however, because of the state of disease progression or the nature of the tumour. Anti-hypercalcaemic therapy is an important palliative measure in cancer patients who have symptoms of hypercalcaemia. Treatment does little to alter the long term prognosis but often results in an improvement in symptoms such that the majority may be made well enough to be discharged from hospital care.
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PMID:Pathogenesis and management of cancer associated hypercalcaemia. 856 93

The objective of this review is to correlate endocrinologic data from mechanistic studies with quantitative histopathology in selected examples of toxic endpoints of the endocrine system in laboratory animals. Mechanistic data can aid in the interpretation of animal toxicology findings and help clarify their significance in risk assessment. Endocrine organs of rodents frequently undergo proliferative changes with advancing age and following chronic exposure to large doses of xenobiotic chemicals, and the sensitivity of rodent endocrine tissues appears to be increasing. Many xenobiotic chemicals in large doses disrupt thyroid function in rodents either by a direct effect on the thyroid influencing synthesis of thyroid hormones or by adversely influencing their peripheral metabolism. A number of chemicals disrupt thyroid function by inhibiting the important enzyme, thyroperoxidase (TPO). A contemporary example of a chemical acting as TPO-inhibitor is sulfamethazine. In short-term mechanistic studies in rats there was a log-dose response relationship in circulating levels of thyroid and pituitary hormones plus a similar non-linear dose-response in morphologic changes in thyroid follicular cells. Endocrinologic data from mechanistic studies and histopathologic/ultrastructural findings will also be presented for the effects of the food color, FDC Red No. 3 (Erythrosine), on the thyroid gland in rats and parathyroid hormone-related protein (a major causative factor in cancer-associated hypercalcemia) on parathyroid chief cells in mice.
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PMID:Correlation of mechanistic data and histopathology in the evaluation of selected toxic endpoints of the endocrine system. 1002 87

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. In the majority of cancer patients, hypercalcemia appears to be a consequence of the tumor production of parathyroid hormone (PTH)-related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy, in contrast to those with primary hyperparathyroidism, have an uncoupled bone turnover, and they usually have low circulating levels of 1.25(OH)2D3. We performed a case-control study to assess the relationship of plasma PTHrP, PTH and 1.25(OH)2D3 with hypercalcemia in cancer patients with a variety of tumors. Sixty of these patients had hypercalcemia, and 45 were normocalcemic. We measured PTHrP and PTH by immunoradiometric assay (Nichols), and 1.25(OH)2D3 by radioreceptor assay (Nichols), in plasma in both groups of cancer patients. Using a logistic regression analysis, we found that the higher PTHrP in plasma, the higher association with hypercalcemia occurred in these patients. In addition, the decreased plasma levels of PTH and 1.25(OH)2D3 in the majority of cancer patients were found to be significantly associated with hypercalcemia. Our results indicate that the combined determination of PTH, PTHrP and 1.25(OH)2D3 in plasma represents a more comprehensive approach to the investigation of hypercalcemia in cancer patients. Our data also support the role of PTHrP as a humoral factor responsible for hypercalcemia in these patients.
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PMID:Parathyroid hormone-related protein, parathyroid hormone, and vitamin D in hypercalcemia of malignancy. 1066 Aug 9

The pathogenesis of cancer-associated hypercalcemia is not yet completely understood. This syndrome appears to be a consequence of the tumor production of humoral factors, mainly parathyroid hormone related protein (PTHrP). However, patients with humoral hypercalcemia of malignancy have features suggesting that factors other than PTHrP might play a role in this syndrome. We performed a case-control study in cancer patients with and without hypercalcemia. A total of 105 patients with a variety of tumors, 60 of them with hypercalcemia (corrected serum calcium over 2.6 mmol/l), and 45 without hypercalcemia. In a previous study, we demonstrated that plasma PTHrP was highly associated with hypercalcemia in these patients. In the present study, we measured the plasma levels of various bone cytokines: interleukin-1beta (IL-1beta), interleukin-6 (IL-6), transforming growth factor (TGF) alpha, and tumor necrosis factor (TNF) alpha, in these cancer patients. We also determined C-terminal type I procollagen (PICP) and C-terminal telopeptide of type I collagen (ICTP), bone formation and bone resorption markers, respectively, in serum in these patients. We found that these osteolytic cytokines do not increase in plasma by the presence of hypercalcemia. In fact, using a logistic regression analysis, a significant (P<0.02) association was found between the low plasma levels of IL-1beta and TGFalpha and hypercalcemia, independent of plasma PTHrP and the presence of bone metastasis, in these patients. No significant association between the plasma levels of IL-6 or TNFalpha and hypercalcemia was found in these cancer patients. Serum ICTP correlated (r=0.35; P=0.008) with hypercalcemia in these patients, but none of the cytokines studied in plasma correlated with either ICTP or PICP in these hypercalcemic patients. Our data indicate that the circulating levels of several bone cytokines are not enhanced by PTHrP in hypercalcemic cancer patients. The mechanism responsible for the association between the low plasma levels of some of these cytokines and hypercalcemia in these patients remains obscure. However, this finding does not rule out the possible local bone effects of these cytokines, contributing to hypercalcemia in cancer patients.
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PMID:Relationship of plasma bone cytokines with hypercalcemia in cancer patients. 1107 64

The homozygous ablation of the gene encoding the PTH/PTHrP receptor (PPR(-/-)) leads to early lethality and limited developmental defects, including an acceleration of chondrocyte differentiation. In contrast to the findings in homozygous PTHrP-ablated (PTHrP(-/-)) animals, these PPR(-/-) mice show an increase in cortical bone, a decrease in trabecular bone, and a defect in bone mineralization. Opposite observations are made in Jansen's metaphyseal chondrodysplasia, a disorder caused by constitutively active PPR mutants, and in transgenic animals expressing one of these receptor mutants (HKrk-H223R) under control of the type alpha1(I) collagen promoter. Expression of the Jansen transgene under the control of the type alpha1(II) collagen promoter was, furthermore, shown to delay chondrocyte differentiation and to prevent the dramatic acceleration of chondrocyte differentiation in PTHrP(-/-) mice, thus rescuing the early lethality of these animals. In the present study we demonstrated that the type alpha1(II) collagen promoter Jansen transgene restored most of the bone abnormalities in PPR(-/-) mice, but did not prevent their perinatal lethality. These findings suggested that factors other than impaired gas exchange due to an abnormal rib cage contribute to the early death of PPR(-/-) mice.
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PMID:Partial rescue of PTH/PTHrP receptor knockout mice by targeted expression of the Jansen transgene. 1171 97


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