UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid adenomas are common benign neoplasms for which no chromosomal defects have been described. We recently found two parathyroid adenomas bearing clonal restriction fragment abnormalities involving the PTH locus, and now show that in one of these tumors: (a) a DNA rearrangement occurred at the PTH locus; (b) the rearrangement separated the PTH gene's 5' flanking region from its coding exons, conceivably placing a newly adjacent gene under the influence of PTH regulatory elements; (c) the DNA that recombined with PTH normally maps to 11q13, the known chromosomal location of several oncogenes and the gene for multiple endocrine neoplasia type I; and (d) the rearrangement was a reciprocal, conservative recombination of the locus on 11q13 (Human Gene Mapping Library assignment D11S287) with PTH (on 11p15). These data provide molecular cytogenetic evidence for the clonal occurrence of a major chromosome 11 aberrancy in this benign parathyroid tumor. The D11S287 clone could prove useful in genetic linkage analyses, in determining precise 11q13 breakpoints in other neoplasms, and in identifying a gene on chromosome 11 that may participate in parathyroid tumor development.
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PMID:Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. 272 71

A rat Leydig cell tumor cDNA library was screened with a 32P-labeled genomic restriction fragment encoding human PTH-like peptide (hPLP), and three cDNA clones were isolated. The largest cDNA insert contained 1146 nucleotides. The cloned cDNA encodes a 177-amino acid protein consisting of a predicted 36-amino acid leader sequence and a 141-amino acid mature peptide in which 9 of 13 amino-terminal residues are identical to rat PTH (rPTH). Comparison of rPLP with hPLP reveals marked conservation of both the nucleotide and amino acid sequences through the prepro, amino-terminal, and midregion portions of the molecules. There is also striking conservation of the 3' noncoding regions of rPLP and hPLP mRNAs, both of which contain AU-rich repeated sequences that may affect mRNA stability. A single species of mRNA of approximately 1.4-kilobases was identified in the rat Leydig cell tumor and in normal rat stomach. Southern blot analysis is consistent with the presence of a single copy of the rPLP gene per haploid genome, and there is no major rearrangement or amplification of the rPLP gene in DNA isolated from the tumor per se. The results demonstrate the presence of a single gene transcript in a rat model of malignancy associated with hypercalcemia which encodes a peptide homologous to hPLP, document the marked interspecies sequence conservation that exists in major functional domains of the mRNAs and peptides, and show the expression of mRNA encoding rPLP in normal stomach as well as in neoplastic rat tissue.
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PMID:Rat parathyroid hormone-like peptide: comparison with the human homologue and expression in malignant and normal tissue. 274 58

We have studied vitamin D metabolism in rats with the transplantable hypercalcemic Walker carcinosarcoma 256, which is a well characterized animal model for humoral hypercalcemia of malignancy. 25-Hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) concentrations were determined in blood samples obtained from parathyroidectomized (PTX) female rats at different time intervals after intramuscular tumor cell inoculation. We observed a dramatic increase in serum 1,25(OH)2D3 (280 +/- 184 vs. 98 +/- 31 pmol/l) 6 days after tumor cell injection and 4 days after the initial rise of serum calcium, whereas 25(OH)D3 tended to decrease. In a separate control experiment we compared this to the effect of exogenous parathyroid hormone in PTX rats and found similar results. In contrast, rats exhibited no change in vitamin D metabolite blood concentration after inoculation of the normocalcemic Yoshida sarcoma, which obviously does not interfere with vitamin D metabolism. We conclude that the humoral bone-resorbing agent produced by the Walker tumor cells causes elevation of serum 1,25(OH)2D3 concentration by this fulfilling an additional criterion of PTH-like activity.
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PMID:The hypercalcemic Walker carcinosarcoma 256 of the rat causes an increase in serum 1,25-dihydroxyvitamin D3. 276 6

For the purpose of determining the significance of CGRP for endocrine tumors, we attempted to establish CGRP radioimmunoassay (RIA) system and to measure plasma CGRP levels in patients with endocrine tumor. One ml of plasma (EDTA-2K + aprotinin 500.KIE/ml) was applied to Sep-Pak C 18 column, and was eluted by 90% MeOH plus 0.1% TFA. The eluted samples were used for RIA. RIA was performed by two day-one day system (delayed assay). B/F separation was made by two Ab-PEG method. Cross-reactivity of antisera was 0.0025% and below 0.0001% against PTH and calcitonin in human, respectively. The standard curve of CGRP showed a dose response curve. Results of dilution and reproduction tests were excellent. Normal range of serum CGRP was 6.7 +/- 3.0 pg/ml (M +/- SD) and the cut-off level was determined to be 12.7 pg/ml. Plasma CGRP showed 128,323 and 2,010 pg/ml in three preoperative patients with medullary thyroid carcinoma, indicating extremely high levels. On the other hand, plasma CGRP levels increased in 2/7, 2/4, 2/5, and 0/3 in patients with parathyroid adenoma, benign insulinoma, carcinoid and pheochromocytoma, respectively. Correlation between CGRP level and calcitonin levels was significant (r = 0.789) in only 16 patients with medullary thyroid carcinoma. This study suggests that our CGRP RIA system was satisfactory for clinical use and measurement of CGRP may be potentially useful for clearing the pathophysiology of neuroendocrine tumors, although CGRP level was raised in patients with medullary thyroid carcinoma.
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PMID:[Radioimmunoassay of plasma calcitonin gene-related peptide (CGRP) levels in patients with endocrine tumor]. 278 8

Studies on the pathogenesis of hypercalcemia in canine lymphosarcoma have led to conflicting results. The biochemical and bone histomorphometric findings in canine lymphosarcoma were examined in 19 hypercalcemic and 17 nonhypercalcemic dogs with lymphosarcoma. Compared to the nonhypercalcemic group, the hypercalcemic dogs demonstrated an increase in fasting and 24-h calcium excretion, an increase in fractional phosphorus excretion, and a significant increase in nephrogenous AMP excretion. Plasma 1,25-dihydroxyvitamin D and immunoreactive PTH levels were equivalent in the two groups. Quantitative bone histomorphometry performed on iliac crest biopsies revealed increased parameters of bone resorption in those hypercalcemic dogs with no evidence of tumor at the biopsy site, without a compensatory increase in bone formation. Acid-urea tumor tissue extracts from eight hypercalcemic and six nonhypercalcemic dogs were examined for adenylate cyclase-stimulating activity (ACSA). All tumors from hypercalcemic dogs contained ACSA, whereas none of the tumors from nonhypercalcemic dogs had ACSA. Further purification of one tumor extract yielded an adenylate cyclase-stimulating protein which appeared to interact specifically with the PTH receptor. We conclude that in some cases, hypercalcemia in canine lymphosarcoma is mediated by a tumor-derived circulating bone-resorbing factor which is distinct from PTH. ACSA detected in tumor tissue appears to be a reliable marker for the syndrome in vivo. The role of this activity in the pathogenesis of the syndrome remains to be determined.
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PMID:Humoral hypercalcemia of malignancy in canine lymphosarcoma. 282 6

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome that appears to be mediated in many instances by a parathyroid hormone-like peptide. Poly(A)+ RNA from a human renal carcinoma associated with this syndrome was enriched by preparative electrophoresis and used to construct an enriched cDNA library in phage lambda gt10. The library was screened with a codon-preference oligonucleotide synthesized on the basis of a partial N-terminal amino acid sequence from a human tumor-derived peptide, and a 2.0-kilobase cDNA was identified. The cDNA encodes a 177 amino acid protein consisting of a 36 amino acid leader sequence and a 141 amino acid mature peptide. The first 13 amino acids of the deduced sequence of the mature peptide display strong homology to human PTH, with complete divergence thereafter. RNA blot-hybridization analysis revealed multiple transcripts in mRNA from tumors associated with the humoral syndrome and also in mRNA from normal human keratinocytes. Southern blot analysis of genomic DNA from humans and rodents revealed a simple pattern compatible with a single-copy gene. The gene has been mapped to chromosome 12.
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PMID:Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. 282 95

In vitro bone resorption induced by tumor extract derived from a hypercalcemic canine adenocarcinoma was significantly inhibited by the PTH receptor antagonist, [Nle8,18,Tyr34]bovine (b) PTH-(3-34) amide. Dose-response curves were prepared for in vitro bone resorption induced in neonatal mouse calvaria by tumor extract, bPTH-(1-34), and prostaglandin E2. A 1:2000-fold ratio of bPTH-(1-34) to [Nle8,18,Tyr34]bPTH-(3-34) amide significantly inhibited bone resorption induced by bPTH-(1-34); however, a 1:10,000 ratio completely antagonized bone resorption. At equivalent potency (1.80-fold stimulation of in vitro bone resorption) of tumor extract compared to bPTH-(1-34), [Nle8,18,Tyr34]bPTH-(3-34) amide (5.0 microM) was capable of significantly reducing in vitro bone resorption. Bone resorption induced by tumor extract (1.35-fold stimulation) was inhibited by [Nle8,18,Tyr34]bPTH-(3-34) amide at concentrations of 5.0 and 1.0 microM. Bone resorption induced by prostaglandin E2 (300 nM) was not inhibited by [Nle8,18,Tyr34]bPTH-(3-34) amide (5.0 microM). These data indicate that [Nle8,18,Tyr34]bPTH-(3-34) amide antagonizes in vitro bone resorption induced by bPTH-(1-34) in a dose-dependent manner and significantly inhibits bone resorption induced by the canine adenocarcinoma model of humoral hypercalcemia of malignancy.
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PMID:Inhibition of in vitro bone resorption by a parathyroid hormone receptor antagonist in the canine adenocarcinoma model of humoral hypercalcemia of malignancy. 283 84

Paraneoplastic production and secretion of peptide hormones by numerous malignant tumours is a well-known phenomenon. The incidence of the production of six peptide hormones was evaluated in patients with acute leukaemia. Most often the calcitonin gene-related peptides were found to be elevated in sera at the time of diagnosis. The values evaluated for the hormones were: h-CT 46.7%, CGRP 51%, s-CT 20.7%, PTH 15.7%, beta-HCG 15%, and ACTH 11.6%. A significant coincidence of two or more hormones was not observed. In 83.4% of the patients increased concentrations of at least one of the six hormones were found. Clinical and biochemical parameters showed no influence on the serum levels of these peptides. Analysis of elevated hormone serum levels in subtypes of leukaemia revealed that the calcitonin-related hormones were significantly correlated to more immature forms of leukaemia such as AUL and M1. Synthesis of calcitonin gene-related peptides was also seen in established leukaemic cell lines and in buffy coat cells of untreated patients with acute leukaemia. This investigation provides further evidence that peptide hormone production in leukaemic blasts is a common finding. These results further suggest hormone production to be a universal concommitant of neoplasia. A possible influence of these peptide hormones on the biological behaviour of the malignant cells is discussed.
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PMID:Peptide hormones in patients with acute leukaemia. 283 99

Human PTH-related protein (hPTHrP) has been characterized as a product of tumor cells with sequence homology to the biologically active amino-terminal portion of human PTH (hPTH). We measured the relative activities of synthetic amino-terminal sequences of hPTH-(1-34) and hPTHrP-(1-34) to stimulate production of cAMP in intact human SaOS-2 osteosarcoma cells. Both peptides enhanced cAMP production at concentrations of 2.5-7.5 X 10(-10) M, had parallel dose-response curves, and were of essentially equal potency. Preincubation of SaOS-2 cells with hPTH-(1-34) or hPTHrP-(1-34) for 1 or 4 h induced homologous desensitization to a second challenge with the same peptide as well as heterologous desensitization to the other PTH peptide, but had little or no effect on the action of vasoactive intestinal peptide; the magnitudes of homologous and heterologous desensitization induced by the same doses of hPTHrP-(1-34) or hPTH-(1-34) were similar. Bone resorption-stimulating activity was measured using 40Ca2+ release from neonatal mouse calvariae in organ culture after 72 h of incubation. hPTHrP-(1-34) gave a dose-response between 0.2 and 5 ng/ml (5 X 10(-11) and 1.2 X 10(-9) M), was about 3 times more potent than Lilly bovine PTH standard (assuming a SA of 3000 U/mg; 100 U/ml), gave the same maximum response as hPTH-(1-34), and was 20-30% as potent as hPTH-(1-34). Neither hPTH-(1-34) nor hPTHrP-(1-34) enhanced prostaglandin production in mouse calvariae, and indomethacin did not inhibit the bone resorption-stimulating activities of either peptide. We conclude that hPTHrP-(1-34) and hPTH-(1-34) have similar high specific biological activities to stimulate production of cAMP in human osteoblast-like cells, but that hPTHrP-(1-34) is modestly less potent than hPTH-(1-34) to stimulate bone resorption in mouse calvariae.
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PMID:Human parathyroid hormone (PTH)-related protein and human PTH: comparative biological activities on human bone cells and bone resorption. 284 88

This investigation addresses a theoretical concept of tumor pathogenesis proposed over 40 years ago, namely that malignancy-associated hypercalcemia can result from endocrine secretion by tumors of a PTH-like factor. These studies demonstrate that a fragment of hHCF alone, without added or tumor-secreted cofactors or hormones, can produce hypercalcemia and other biochemical abnormalities associated with HHM. The hypercalcemia can be generated by hHCF-(1-34)NH2 action on bone, although kidney and gut could contribute to the HHM syndrome when it occurs naturally. No other tumor-secreted peptide displays this biological profile. These studies establish one (PTH-like) mechanism by which human tumors could produce hypercalcemia. Furthermore, the finding that hHCF-(1-34)NH2 is more potent than PTH in some systems is of considerable interest for the future design of hormone analogs. A broad spectrum of biological properties of hHCF-(1-34)NH2, including production of components of the HHM syndrome, can be inhibited by a PTH antagonist. Because [Tyr-34]bPTH-(7-34)NH2 selectively and competitively occupies PTH receptors, our studies demonstrate formally that hHCF-(1-34)NH2 mediates some (and perhaps all) of its actions via receptors conventionally regarded as intended for interaction with PTH, but which actually may be present to allow for expression of bioactivity of both secreted proteins. Although some structural homology is shared by the two hormones and many contribute to interaction with receptors, the disparity in structure, especially within the 1-34 domains responsible for bioactivity in both hormones, is more pronounced. The similarity in biological profiles despite structural differences between hHCF and PTH is emphasized by the inhibitory action of [Tyr-34]bPTH-(7-34)NH2 against the tumor peptide even in the absence of much of the homologous region in the PTH antagonist. This investigation provides impetus for designing more potent antagonists, which must now be regarded more appropriately as inhibitors of both PTH and hHCF. Such antagonists may best be generated from hybrid structures of the two hormones. In any case, these studies establish a promising new approach to therapy of tumor-associated hypercalcemia.
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PMID:A tumor-secreted protein associated with human hypercalcemia of malignancy. Biology and molecular biology. 285 15

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