Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

mRNA coding for pre-pro-PTH, a precursor of PTH, was sought in an apparently nonfunctioning parathyroid carcinoma that had transformed from one that was previously functioning. Total poly(A+) RNA was prepared by phenol-chloroform-isoamyl alcohol extraction and oligo-dT-cellulose affinity chromatography from the tumor tissue and bovine parathyroid glands. In the rabbit reticulocyte lysate cell-free translation system, total poly(A+) RNA from the tumor as well as that from bovine parathyroid glands directed the translation of a product which was specifically precipitated by an anti-PTH serum and which migrated at the same position as pre-pro-PTH on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These results indicated the presence of mRNA coding for pre-pro-PTH (PTH mRNA) in an apparently nonfunctioning parathyroid carcinoma, suggesting that PTH synthesis is not always absent in parathyroid carcinomas which are not accompanied by hyperparathyroidism.
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PMID:Identification of parathyroid hormone messenger ribonucleic acid in an apparently nonfunctioning parathyroid carcinoma transformed from a parathyroid carcinoma with hyperparathyroidism. 286 4

A family of multiple endocrine neoplasia type I with five confirmed cases in three generations is described. All of them have primary hyperparathyroidism in common. The propositus is 51 year-old male. After a year of symptoms of gastroduodenal ulcer, he was found to have elevated levels of serum gastrin and PTH. The serial imaging studies revealed a tumor in pancreatic head, and Zollinger-Ellison syndrome was diagnosed. The gastrin level was reduced into normal range after extirpation of the tumor, but post surgical elevation of Calcium put the patient under parathyroidectomy, which normalized serum PTH and Calcium levels. His two sisters (I and II), the mother of them, and the daughter of sister I, had neither signs nor symptoms until family study showed hypercalcemia in all. Sister I is a 54 year-old female with enlarged parathyroid. The hyperparathyroidism is of chemical type, but no other endocrinological abnormality is found. The Calcium level decreased after parathyroidectomy. Sister II is a 56 year-old female. The only sign was galactorrhea. Serum PTH and Calcium decreased after parathyroidectomy. The prolactinoma was diagnosed by the increased prolactin levels and enhanced mass lesion in sella turcica. Her serum prolactin levels is now within normal range since she is on bromocryptine. The mother of the above three siblings and the daughter of the sister I are now under further study.
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PMID:[A family with multiple endocrine neoplasia type I presenting prolactinoma, Zollinger-Ellison syndrome and hyperparathyroidism]. 286 39

The effects of 3-amino-1-hydroxy-propylidene-1,1-bisphosphonate (AHPrBP), 1-hydroxyethylidene-1,1-bisphosphonate (HEBP), dichloromethylenebisphosphonate (Cl2MBP) and azacycloheptylidene-2,2-bisphosphonate (AHBP) on bone were examined in organ culture using newborn mice calvaria. AHPrBP, HEBP and Cl2MBP caused a dose-dependent inhibition of PTH-stimulated (10 nmol/l) release of 45Ca from the calvaria, at and above a concentration of 3 mumol/l, whereas AHBP only caused a slight inhibition, at and above 100 mumol/l. AHPrBP inhibited PTH-stimulated release of 3H from bones prelabelled with [3H]-proline. AHPrBP (30 mumol/l) diminished the stimulatory effect of 1 alpha(OH)vitamin D3 (10 nmol/l), prostaglandin E2 (0.1 mumol/l) and renal tumor conditioned media on 45Ca release. AHPrBP and Cl2MBP, at and above 3 mumol/l, decreased PTH-stimulated mobilization of Ca2+ and Pi and in parallel the release of beta-glucuronidase without affecting the release of lactate dehydrogenase. The inhibitory effect of AHPrBP (30 mumol/l) on PTH-induced 45Ca release was irreversible. The inhibition by AHPrBP (30 mumol/l) on spontaneous and PTH-stimulated release of 45Ca can be seen first after 24 h of culture. Similarly the inhibitory effect by HEBP (30 mumol/l) and Cl2MBP (30 mumol/l) was delayed and could be observed after 36 and 24 h of culture, respectively. PTH-stimulated release of Ca2+, Pi, beta-glucuronidase and beta-N-acetylglucosaminidase was reduced by AHPrBP first after 24 h of culture. AHPrBP, HEBP and Cl2MBP, at concentrations which are inhibitory on bone resorption, do not affect protein synthesis and mitotic activities in mouse calvaria. These data show that AHPrBP, HEBP and Cl2MBP inhibit bone resorption in vitro and in parallel decrease lysosomal enzyme release by a mechanism, which is not related to cytotoxicity. In addition, the delayed inhibitory effect on bone resorption and lysosomal enzyme release by all the compounds suggest that bisphosphonates inhibit bone resorption indirectly and not by a direct effect on existing osteoclasts. The delayed inhibition by bisphosphonates on bone resorption may be due to decreased recruitment of new osteoclasts as a consequence of an inhibitory action on mononuclear osteoclast precursor cells.
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PMID:Effects of four bisphosphonates on bone resorption, lysosomal enzyme release, protein synthesis and mitotic activities in mouse calvarial bones in vitro. 295 2

The Rice-500 Leydig cell tumor of Fischer rats is associated with humoral hypercalcemia in vivo and produces a factor that stimulates cAMP formation in cultured rat osteosarcoma cells. We found that cultured human skin fibroblasts respond to both human PTH-(1-34) and the factor produced by cultured rat Leydig tumor cells with a dose-dependent rise in cAMP formation. The time courses for stimulation of the two agents were similar, and stimulation by both was blocked by the competitive PTH antagonist [8,18-norleucine,34-tyrosine]bovine PTH-(3-34) amide. These data suggest that PTH-like factors secreted by a murine tumor are capable of interacting with the human PTH receptor.
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PMID:A factor produced by cultured rat Leydig tumor (Rice 500) cells associated with humoral hypercalcemia stimulates adenosine 3',5'-monophosphate production via the parathyroid hormone receptor in human skin fibroblasts. 298 87

PTH receptor-stimulating proteins may be a common mediator of humoral hypercalcemia of malignancy (HHM). Such proteins exhibit adenylate cyclase-stimulating activity (ACSA) in PTH-sensitive assays, and ACSA has been used to follow their purification. Acid/urea tumor extracts from a murine squamous carcinoma model of HHM were previously shown to have very high ACSA, which was partially, but incompletely, inhibited by the PTH antagonist Nle8,18,Tyr34-bovine PTH-(3-34) amide. ACSA from murine tumor extracts has now been further purified using solvent fractionation and reverse phase HPLC. Approximately half of the ACSA is attributable to a family of three proteins (peaks IA, IB, and IC) with properties characteristic of the PTH receptor-stimulating protein extracted from rat Leydig cell and human HHM tumors. The ACSA in these three peaks of murine tumor extract elutes in the same region as human tumor ACSA on reverse phase HPLC, has a dose-response curve parallel to that of PTH, and is fully inhibited by the PTH-(3-34) antagonist in both the renal cortical and rat osteosarcoma (ROS) adenylate cyclase assays. The remaining half of the ACSA from murine tumor extracts elutes as a single peak (peak II) at a higher acetonitrile concentration on reverse phase HPLC. In the renal cortical assay, its dose-response curve differs from that of PTH, its ACSA is not affected by the PTH-(3-34) antagonist, and it potentiates PTH- or peak I-stimulated adenylate cyclase activity. In the PTH-sensitive intact cell ROS assay, peak II exhibits no ACSA. We conclude that the potent ACSA of murine tumor acid/urea extract results in large part from amplification of the PTH-specific ACSA (peak I) by peak II. Peak II is a distinct protein, not previously reported in tumor extracts, that may act as a postreceptor step in the adenylate cyclase system.
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PMID:Two species of adenylate cyclase-stimulating activity in a murine squamous carcinoma model of humoral hypercalcemia of malignancy. 300 44

When grown as sc tumors in the nude (nu/nu) mouse, cells of the established human renal carcinoma cell line 786-0 produce hypercalcemia; this has an apparent humoral basis because it is reversed by resection of the primary tumor. We have investigated the pathogenesis of hypercalcemia in this model. Tumor-bearing mice were hypercalcemic (13.4 +/- 0.9 vs. 9.52 +/- 0.13 mg/dl in control mice) and hypophosphatemic (10.0 +/- 0.8 vs. 13.8 +/- 1.5 mg/dl in control mice; all values are mean +/- SEM). The serum concentration of 1,25-dihydroxyvitamin D was increased in tumor-bearing animals (70.0 +/- 9.3 vs. 43.8 +/- 4.8 pg/ml in control animals). Urinary excretion of cAMP was similar in control (33.7 +/- 1.4 nmol/mg creatinine) and tumor-bearing mice (38.2 +/- 4.7 nmol/mg creatinine). However, in the latter, the acute response of urinary cAMP to PTH was blunted. Although intestinal calcium transport in everted duodenal sacs in vitro was increased in tumor-bearing mice, hypercalcemia was unaffected by feeding the animals for 8 days a diet containing less than 0.02% calcium. Hence, absorption of dietary calcium did not play a significant role in maintenance of hypercalcemia. In hypercalcemic animals, the calcium content of the humerus was decreased (2.95 +/- 0.08 vs. 3.29 +/- 0.13 mg in controls; P less than 0.05). Quantitative histomorphometric analysis of the distal femoral metaphysis disclosed a significant reduction in trabecular bone volume in tumor-bearing mice (12.0 +/- 1.1% vs. 16.1 +/- 1.1% in controls; P less than 0.02). A strong trend for increased osteoclast surface and number was observed, suggesting that bone resorption was increased. Osteoblast surface and number were also somewhat increased, as was the rate of mineral apposition (2.55 +/- 0.14 vs. 1.91 +/- 0.04 micron/day in controls; P less than 0.01). Thus, the decrease in trabecular bone volume was associated with high turnover of bone, with an apparent net increase in bone resorption. We conclude that hypercalcemia in the nude mouse bearing human renal carcinoma cells is associated with increased bone resorption, high bone turnover, hypophosphatemia, and increased serum levels of 1,25-dihydroxyvitamin D.
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PMID:Pathogenesis of hypercalcemia in nude mice bearing a human renal carcinoma. 301 91

We found previously that a human renal carcinoma cell line derived from a hypercalcemic patient induces humoral hypercalcemia when grown as allografts in the nude mouse and secretes a protein that activates adenylate cyclase via the PTH receptor. The purpose of this study was to examine the conditioned medium of this cell line for bone-resorbing activity in vitro. Processed conditioned medium produced dose-dependent stimulation of bone resorption in cultured fetal rat limb bone explants. Two PTH antagonists were used to assess the PTH receptor dependence of this bone-resorbing activity. Neither [8Nle,18Nle,34Tyr]bovine (b) PTH-(3-34) amide nor [34Tyr]bPTH-(7-34)amide inhibited bone resorption or limb bone cAMP accumulation induced by either processed conditioned medium or equivalent concentrations of bPTH-(1-34). As an alternate means to assess whether this tumor-derived PTH-like protein had intrinsic bone-resorbing activity, the latter was measured during partial purification of PTH-like adenylate cyclase-stimulating activity (ACSA) from conditioned medium by consecutive gel filtration and reverse phase HPLC. The bone-resorbing activity in conditioned medium could not be resolved from PTH-like ACSA by these two separation techniques, indicating that the activities may be intrinsic to the same protein. These results are consistent with the view that a tumor-derived protein with PTH-like ACSA and bone-resorbing activity may be responsible for hypercalcemia in vivo.
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PMID:Parathyroid hormone-like adenylate cyclase-stimulating activity from a human carcinoma is associated with bone-resorbing activity. 302 77

Tl-201/I-123 subtraction scintigraphy was performed in 17 patients with clinical symptoms and biochemical measurements suggestive of primary hyperparathyroidism. Nineteen abnormal sites were identified. These results were correlated with PTH measurements and surgical findings. Three sites were considered unrelated to the parathyroid glands, two corresponding to palpable thyroid nodules and one to muscle uptake of unknown origin. One scintigram did not reveal either of two abnormal glands while two others were considered falsely positive in view of surgical failure. Fourteen sites corresponded to abnormal parathyroid gland at surgery; five glands, weighing more than 2000 mg, could be correctly located on the Tl-201 scintigraphy prior to the subtraction procedure; six glands, weighing between 500 and 2000 mg, were easily localized after the subtraction procedure; three glands, weighing between 180 and 200 mg, were correctly localized after further manipulation of the subtraction procedure. In a patient with parathyroid hyperplasia, one gland, weighing 150 mg, was not located and another was not found upon surgery. Overall sensitivity was 87.5%. A positive correlation between PTH levels, tumor weight, and ease of detection on scintigraphy was found. This correlation was particularly useful in excluding large abnormal uptake related to thyroid disorder or artifact. The results suggest that Tl-201/I-123 parathyroid scintigraphy could become an alternative to Tl-201/Tc-99m parathyroid scintigraphy, with possibly improved detection of low weight abnormal parathyroid glands.
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PMID:Localization of abnormal parathyroid gland(s) using thallium-201/iodine-123 subtraction scintigraphy in patients with primary hyperparathyroidism. 302 92

Collagenases that specifically cleave native collagen at neutral pH have been implicated in the maintenance and turnover of connective tissue. In bone, the origin of neutral collagenase has remained equivocal, although recent studies have indicated that it is synthesized by the osteoblast. In the present work, regulation of secretion of neutral collagenase and a collagenase inhibitory activity was investigated using the osteoblastic tumor cell line UMR 106-01 and a variety of bone-resorbing agents. Under basal conditions, UMR 106-01 cells produced very low levels of collagenase but substantial amounts of the inhibitory activity. Exposure to PTH and, to a lesser extent, 1,25-dihydroxyvitamin D3, prostaglandin E2, retinoic acid, and epidermal growth factor stimulated the release of collagenase, an effect not seen with interleukin-1 or heparin. The stimulation of collagenase by PTH was dose dependent, with a half-maximal response occurring at 10(-8) M. Inclusion of isobutylmethylxanthine decreased the concentration of PTH required to produce half-maximal stimulation to 2 X 10(-10) M, indicating action via cAMP. With respect to the inhibitory activity, PTH and epidermal growth factor were the only agents, among those tested, able to enhance its production. Both hormones caused a 50-100% increase over control levels 72 h after hormone administration. There were notable differences in the time courses of production of collagenase and the inhibitor. After treatment with PTH, the enzyme reached maximal concentrations between 12-48 h, but declined to undetectable levels by 96 h. In contrast, the inhibitory activity was secreted in a linear fashion, with the highest concentrations achieved around 72-96 h. These results suggest a complex pattern of regulation of collagenase and inhibitor secretion by the osteoblastic cell, with the steady accumulation of inhibitor perhaps being responsible for the ultimate curtailment of enzyme activity.
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PMID:Hormonal regulation of the production of collagenase and a collagenase inhibitor activity by rat osteogenic sarcoma cells. 303 74

Human tumors and keratinocyte-conditioned medium contain PTH-like adenylate cyclase-stimulating proteins. Human dermal fibroblasts have receptors that recognize PTH and a factor associated with humoral hypercalcemia of malignancy in rats. We examined 10 human dermal fibroblast lines for an adenylate cyclase response to PTH. Six of 10 lines tested displayed a definite response (2.4- to 3.8-fold over basal) to 10(-6) M bovine PTH-(1-34). This response was inhibited by the PTH analog and antagonist Nle8,18,Tyr34-bPTH-(3-34). We also examined whether human dermal fibroblasts are capable of responding to either a human PTH-like tumor-derived factor or the PTH-like factor contained in human keratinocyte-conditioned medium. Both human humoral hypercalcemia of malignancy-associated tumor extract (2.5 X 10(-10) M) and keratinocyte-conditioned medium (8 X 10(-10) M) stimulated human dermal fibroblast adenylate cyclase. These concentrations are markedly lower than those required for PTH-induced adenylate cyclase stimulation. This activity was also inhibited by the PTH analog. The high prevalence of PTH-responsive adenylate cyclase in dermal fibroblast lines and the apparent potency of tumor-derived and keratinocyte-derived PTH-like factors in dermal fibroblasts suggest that these factors may play a role in normal dermal physiology.
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PMID:Skin-derived fibroblasts respond to human parathyroid hormone-like adenylate cyclase-stimulating proteins. 303 48


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