Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to examine the effects of IL-1 beta on integrin expression in MG-63 human osteosarcoma cells. Human recombinant IL-1 beta (rIL-1 beta) produced significant increases in both alpha 2- and alpha 5-subunit mRNA levels, as well as a smaller increase in alpha v-subunit mRNA. In contrast, IL-1 beta decreased alpha 4-subunit mRNA levels by approximately 30% relative to untreated controls. These findings suggest that human IL-1 beta differentially regulates expression of integrins. When cultures were treated with both IL-1 beta and the cyclooxygenase inhibitor, indomethacin, the expression of alpha 2-, alpha 5-, and alpha v-subunit mRNA levels were dramatically increased relative to untreated controls; co-treatment with 0.5 mM prostaglandin E2 (PGE2) partially reversed this effect. Indomethacin alone did not affect integrin mRNA levels. Treatment with IL-1 beta or IL-1 beta + indomethacin also induced significant changes in MG-63 morphology (i.e., increased cell elongation) and increased the ability of cells to contract collagen gels. PGE2 reversed the above effects on cell morphology and gel contraction. These findings indicate that (a) IL-1 beta differentially regulates the expression of integrins and (b) that PGE2, which is induced by IL-1 beta, may provide a negative feedback loop which counteracts the stimulatory effect of IL-1 beta on integrin gene expression. It is suggested that products of inflammation may affect cell behavior by differentially regulating the expression of various integrins.
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PMID:IL-1 beta and prostaglandins regulate integrin mRNA expression. 174 14

We have previously reported that vasoactive intestinal peptide (VIP) stimulates bone resorption in organ culture via a cAMP-dependent mechanism. Here we describe functional receptors for VIP on a clonal line of human osteosarcoma cells, SaOs-2. SaOs-2 cells respond to VIP with an increase in cAMP. The effect was rapid (2 min) and dose dependent from 0.15-15 nM VIP, with half-maximal stimulation at 1.4 nM. SaOs-2 cells produce prostaglandin E2 (PGE2) and respond to exogenous PGE2 with increases in cAMP approximately one third as great as those induced by VIP. However, the VIP-stimulated increases in cAMP occurred without detectable increases in PGE2 production, and increases in cAMP were unaffected by the cyclooxygenase inhibitor indomethacin. SaOs-2 cells pretreated with VIP for 24 h were significantly less responsive to a second acute challenge with VIP, but retained their ability to respond to PGE2. Similarly, pretreatment with PGE2 induced homologous desensitization to PGE2, but had no effect on the VIP-stimulated increase in cAMP. These patterns of response paralleled those previously described in whole bone in organ culture. Binding studies with [125I]VIP demonstrated specific, saturable, high affinity receptors for VIP on SaOs-2 cells. Scatchard analysis of [125I]VIP binding at 37 C resulted in a curvilinear plot. Analysis based upon the assumption of two independent binding sites gave Kd values of 0.44 and 17 nM for high and low affinity binding sites, respectively. The numbers of high and low affinity sites per cell were determined to be 8,500 and 57,000, respectively. Binding of [125I]VIP was partially inhibited by two related peptides, secretin and PHI-27, but not by PTH, calcitonin or a variety of unrelated peptides. We conclude that the action of VIP on human SaOs-2 cells is similar to that observed in intact mouse calvaria, and that these cells provide a good model for the study of the initial steps of VIP action in bone.
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PMID:Functional receptors for vasoactive intestinal peptide on human osteosarcoma cells. 632 42

The metabolism of arachidonic acid to its cyclo-oxygenase products was studied in monolayer cultures of osteoblast-rich rat calvarial cells and of clonal cell lines from a rat osteogenic sarcoma, enriched in the osteoblast phenotype. Prostanoids were measured by radioimmunoassay after extraction of media and fractionation by high pressure liquid chromatography. In both normal and malignant osteoblasts the major cyclooxygenase product was 6-oxo-prostaglandin F1 alpha, the hydration product of prostacyclin, with lesser amounts of prostaglandin E2 and prostaglandin F2 alpha. No significant thromboxane B2 was detected. Prostaglandins are thought to have a local role in the regulation of bone resorption. These results point to the possible importance of prostacyclin either in bone resorption or in some other local function, e.g., regulation of bone blood flow.
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PMID:Cyclo-oxygenase products of arachidonic acid metabolism in rat osteoblasts in culture. 640 86

Amine-carboxyboranes have been shown to prevent osteoporosis and loss of bone mass in rodents. In vitro studies using CF1 mouse pup calvaria and rat UMR-106 osteosarcoma cells showed that amine-carboxyborane derivatives reduced significantly the loss of intracellular calcium into the growth medium from 10(-4) to 10(-8) M over 48 hours. Amine-carboxyborane derivatives were more effective than calcitonin or simple boron salts. Calcium incorporation into these cells and proline incorporation into collagen was accelerated in the presence of amine carboxyboranes. The amine-carboxyborane derivatives effectively inhibited lysosomal and proteolytic enzymes as well as activities of serine elastase, prostaglandin cyclooxygenase, and 5'-lipoxygenase in mouse macrophages, human PMNs, leukocytes and Be Sal cells. IC50 values were in the range of 10(-6) M. In lactating ovariectomized female rats after administered amine-carboxyboranes for 14 days at 8 mg/kg/day orally, the femur and humerus showed increased volume, weight, density and ash weight. Serum calcium levels were elevated significantly with minimum reductions on serum inorganic phosphate levels. Femur calcium levels were elevated after treatment with amine-carboxyborane derivatives, but not with etidronate. Humerus total lipids after 14 days were slightly elevated probably due to increased levels of triglycerides and phospholipids.
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PMID:The anti-osteoporotic activity of amine-carboxyboranes in rodents. 764 84

The effects of interleukin-1 alpha (IL-1 alpha) on arachidonic acid (AA) metabolism were studied in the human osteosarcoma cell lines, G292 and SaOS-2. The cells were prelabeled with 3H-arachidonic acid. Radiolabeled metabolites were measured by reversed-phase high-pressure liquid chromatography with a radioactive detector. Indomethacin inhibited prostaglandin E2 (PGE2) production without affecting lipoxygenase (LO) products in G292 cells. In the G292 cells, IL-1 alpha (50 U/ml) induced a 10-fold increase in PGE2 production at all the incubation times tested, and a significant two-fold increase in 5 hydroxyeicosatetraenoic acid (HETE) formation after 48 h. These effects were not seen in SaOS-2 cells under identical conditions. These results suggest that, although some osteosarcomal cell lines may not respond directly to IL-1 with effects on AA metabolism, the mechanism of its action in others may involve modulation of both cyclooxygenase (CO) and LO pathways.
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PMID:Effects of interleukin-1 alpha on arachidonic acid metabolism in human osteosarcoma osteoblastic cells. 839 96

The production of prostaglandins by osteoblasts is an important mechanisms for the regulation of bone turnover. Bone cells contain both inducible and constitutive prostaglandin G/H synthase (PGHS-2 and PGHS-1) and these are differentially regulated. Nonsteroidal anti-inflammatory drugs (NSAIDs), which selectively inhibit one of these enzymes, would be useful in assessing their relative roles in bone metabolism. By Northern analysis, only PGHS-2 is expressed by the immortalized rat osteoblastic cell line, Py1a, while only PGHS-1 is expressed by the rat osteosarcoma cell line, ROS 17/2.8. We tested the relative inhibitory potency (IC50) of seven different NSAIDs on these two cell lines. A recently described selective inhibitor of PGHS-2, NS-398, was approximately 30 times more potent in inhibiting PGHS-2 than PGHS-1, and diclofenac was approximately 10 times more potent. Both had IC50's of approximately 3 nM for PGHS-2 in Py1a cells. Indomethacin, flurbiprofen, naproxen, and piroxicam were relatively nonselective with IC50's ranging from 30 nM to 1 microM, while 6-methoxy-2 naphthyl acetic acid, the active metabolite of nabumetone, was inhibitory only at concentrations greater than 1 microM. These results indicate that the presently available NSAIDs are unlikely to distinguish completely between effects mediated by PGHS-2 or PGHS-1. However, the cell systems employed could provide a model for the analysis of new compounds with greater selective activity.
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PMID:Differential effects of nonsteroidal anti-inflammatory drugs on constitutive and inducible prostaglandin G/H synthase in cultured bone cells. 925 49

We have previously shown that an exogenous type I collagen matrix can regulate expression of mRNA for parathyroid hormone (PTH)-related protein (PTHrP) and its receptor, the PTH/PTHrP receptor, in the UMR106-06 osteogenic sarcoma cell line, which is considered to be representative of a relatively mature osteoblast phenotype. Consistent with those data, we show here that growth of UMR106-06 cells on type I collagen increased PTH/PTHrP receptor-binding capacity. Analysis of the binding data showed that the number of PTH/PTHrP receptors expressed by cells cultured on collagen was at least 2-fold greater than that of cells cultured on plastic. Expression of mRNA encoding alkaline phosphatase (ALP) and osteopontin (OP) was also upregulated in cells cultured on collagen, suggesting that interaction with collagen promotes the osteoblast phenotype in this cell line. Retinoic acid (RA), which has also been shown to promote osteoblastic differentiation, synergized with type I collagen to cause super-induction of OP mRNA. In contrast, RA abolished the collagen-induced increase in ALP mRNA and PTH/PTHrP receptor mRNA. The collagen-mediated increase in the expression of OP and PTH/PTHrP receptor mRNA, but not that of ALP, was perturbed by prior covalent modification of the collagen by non-enzymatic glycation. The collagen effects did not occur via interaction with RGD amino acid domains in type I collagen, but evidence was obtained for involvement of the DGEA amino acid cell-binding domain. The mechanism by which plating of UMR106-06 cells on a type I collagen substrate affects PTH/PTHrP receptor mRNA levels was investigated. Inhibition of cytoskeletal organization using cytochalasin D, and inhibitors of protein phosphatases, protein kinase C, phospholipase C and cyclooxygenase, did not abrogate the collagen-mediated effects. In contrast, treatment of cells with the protein tyrosine kinase inhibitor genistein, but not herbimycin A, dose-dependently abolished the collagen effects on the expression of PTH/PTHrP receptor, ALP and OP mRNA. These results show that a type I collagen substrate influences the expression of osteoblast-associated genes in a cell model of mature osteoblasts and suggests that this involves, at least in part, changes in intracellular tyrosine phosphorylation.
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PMID:Type I collagen influence on gene expression in UMR106-06 osteoblast-like cells is inhibited by genistein. 984 67

The paper analyzes the data of long-term studies made in the N. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences. The study dealt with androgen exchange, the baseline levels of serum sexual steroid hormones and their receptors in the tumor, the blood concentrations of the sexual steroids conjugated globulin and pituitary hormone, the metabolism of arachidonic acid, the expression of epidermal growth factor and its ligands, the amount of calmodulin, cAMP in the osteogenic sarcoma in 300 patients aged 14-56 years. Analyzing the findings suggests that there are some directions in studies, development, and practical introduction of new pathogenetic therapies of osteosarcoma, which are associated with the regulation of androgen exchange, the correction of the cyclooxygenase pathway of arachidonic acid, expression of receptors of epidermal growth factor and its ligands in the tumor.
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PMID:[Hormones and auto-paracrine tumor growth regulators in osteogenic sarcoma]. 998 64

The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and that COX-1 is the major isoform responsible for the production of prostaglandins (PGs) in the gastrointestinal tract have provided a rationale for the development of specific COX-2 inhibitors as a new class of anti-inflammatory agents with improved gastrointestinal tolerability. In the present study, the preclinical pharmacological and biochemical profiles of rofecoxib [Vioxx, also known as MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], an orally active COX-2 inhibitor, are described. Rofecoxib is a potent inhibitor of the COX-2-dependent production of PGE(2) in human osteosarcoma cells (IC(50) = 26 +/- 10 nM) and Chinese hamster ovary cells expressing human COX-2 (IC(50) = 18 +/- 7 nM) with a 1000-fold selectivity for the inhibition of COX-2 compared with the inhibition of COX-1 activity (IC(50) > 50 microM in U937 cells and IC(50) > 15 microM in Chinese hamster ovary cells expressing human COX-1). Rofecoxib is a time-dependent inhibitor of purified human recombinant COX-2 (IC(50) = 0.34 microM) but caused inhibition of purified human COX-1 in a non-time-dependent manner that could only be observed at a very low substrate concentration (IC(50) = 26 microM at 0.1 microM arachidonic acid concentration). In an in vitro human whole blood assay, rofecoxib selectively inhibited lipopolysaccharide-induced, COX-2-derived PGE(2) synthesis with an IC(50) value of 0.53 +/- 0.02 microM compared with an IC(50) value of 18.8 +/- 0.9 microM for the inhibition of COX-1-derived thromboxane B(2) synthesis after blood coagulation. Using the ratio of the COX-1 IC(50) values over the COX-2 IC(50) values in the human whole blood assay, selectivity ratios for the inhibition of COX-2 of 36, 6.6, 2, 3, and 0.4 were obtained for rofecoxib, celecoxib, meloxicam, diclofenac, and indomethacin, respectively. In several in vivo rodent models, rofecoxib is a potent inhibitor of carrageenan-induced paw edema (ID(50) = 1.5 mg/kg), carrageenan-induced paw hyperalgesia (ID(50) = 1.0 mg/kg), lipopolysaccharide-induced pyresis (ID(50) = 0.24 mg/kg), and adjuvant-induced arthritis (ID(50) = 0.74 mg/kg/day). Rofecoxib also has a protective effect on adjuvant-induced destruction of cartilage and bone structures in rats. In a (51)Cr excretion assay for detection of gastrointestinal integrity in either rats or squirrel monkeys, rofecoxib has no effect at doses up to 200 mg/kg/day for 5 days. Rofecoxib is a novel COX-2 inhibitor with a biochemical and pharmacological profile clearly distinct from that of current nonsteroidal anti-inflammatory drugs and represents a new therapeutic class of anti-inflammatory agents for the treatment of the symptoms of osteoarthritis and rheumatoid arthritis with improved gastrointestinal tolerability.
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PMID:Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. 1041 62

The purpose of this study was to determine the PGE2 concentration in naturally-occurring cancer in pet dogs and in canine cancer cell lines in order to identify specific types of canine cancer with high PGE2 production which could serve as preclinical models to evaluate anticancer strategies targeting PGE2. PGE2 concentrations were measured by enzyme immunoassay in canine melanoma, soft tissue sarcoma, transitional cell carcinoma, osteosarcoma, and prostatic carcinoma cell lines; in 80 canine tumor tissue samples including oral melanoma (MEL), oral squamous cell carcinoma (SCC), transitional cell carcinoma of the urinary bladder (TCC), lymphoma (LSA), mammary carcinoma (MCA), osteosarcoma (OSA), prostatic carcinoma (PCA); and in corresponding normal organ tissues. High concentrations of PGE(2)(range 400-3300 pg/10(4)cells) were present in cell culture medium from the transitional cell carcinoma, prostatic carcinoma, and osteosarcoma cell lines. PGE2 concentrations in tumor tissues were elevated (tumor PGE2 concentration>mean+2X sd PGE(2)concentration of normal organ tissue) in 21/22 TCC, 5/6 PCA, 7/10 SCC, 5/10 MEL, 3/8 MCA, 4/15 OSA, and 0/9 LSA. Results of this study will help guide future investigations of anticancer therapies that target cyclooxygenase and PGE2.
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PMID:Prostaglandin E2 concentrations in naturally occurring canine cancer. 1116 79


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