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 concentration in plasma of 15 fasting amino acids were measured in 14 control volunteers and 55 cancer patients. In addition, 16 patients (7 with, 9 without total parenteral nutrition [TPN] ) with metastatic sarcoma had sequential amino acid profiles measured during 6 weeks of ablative chemotherapy. In four cancer patient groups (lymphoma, sarcoma, osteosarcoma and metastatic sarcoma) with no or minimal weight loss, most plasma amino acid levels were similar to controls. Proline levels were significantly reduced in the lymphoma and sarcoma patients. Esophageal cancer patients with 20% body weight loss had a marked reduction in total and individual amino acid levels (except branched chain amino acids) compared to controls and all others. The metastatic sarcoma patients who received parenteral nutrition had higher levels of plasma lysine and tyrosine during chemotherapy than controls; however, TPN failed to change the majority of amino acid levels. It appears that plasma amino acid levels except proline were well maintained in cancer patients without weight loss. Esophageal cancer patients with weight loss demonstrated marked reduction in all circulating amino acids except branched chain. Parenteral nutrition did not significantly alter the amino acid profile of cancer patients undergoing chemotherapy.
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PMID:Fasting plasma amino acid levels in cancer patients. 392 95

Poly I:C/poly-L-lysine (poly ICL) was effective in preventing or delaying the development of osteogenic sarcoma (OGS) in mice. C57BL/6J mice were inoculated subcutaneously with 5 X 10(4) OGS cells and treatment was evaluated by palpable tumor development and subsequent day of death. A significant antitumor effect resulted from injection of 150 microgram of poly ICL into the tumor site starting immediately after tumor implant and followed by four subsequent treatments. Seventy percent of treated animals remained tumor free at 50 days, a time at which 70% of placebo treated animals had died as a result of tumor development. A similar treatment regimen of mice inoculated with 2 X 10(5) OGS cells resulted in a significant delay of time to tumor and subsequent day of death. Treatments with poly ICL were ineffective if they were initiated after development of palpable tumor or if they were administered at a nontumorous site on the animal. These findings indicate that the optimal therapy resulted from repeated intratumor treatment prior to development of extensive tumor burden.
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PMID:Effect of poly I:C/poly-L-lysine (poly ICL) on the development of murine osteogenic sarcoma. 657 30

Plasmin (Pm) is a broad action serine protease implicated in numerous physiological functions. In bone, Pm may play a role in growth, resorption, metastasis, and the activation of growth factors. The various components of the Pm system are known to bind and function on the cell surface of various cell types, but no pertinent data are available describing membrane-bound Pm or its zymogen, plasminogen (Pg), in either normal or neoplastic bone cells. We report here that Pg binds to the surface of the human osteosarcoma cell line MG-63 and is activated to Pm by endogenous urokinase plasminogen activator (uPA). These conclusions are based on experiments utilizing radiolabeled compounds and a cell surface proteolytic assay measuring amidolytic activity of Pm. 125I-Pg binding to cells was time dependent, saturable, reversible, and specific. Binding was characterized by a relatively low affinity (Kd approximately 0.9 microM) and a high capacity (approximately 7.5 x 10(6) sites/cell). The binding of 125I-Pg was associated with lysine binding sites of the plasminogen molecule. Activation of 125I-Pg to 125I-Pm occurred on the cell surface and was dependent upon cell bound uPA, as determined by inhibitory antibodies. Binding of Pg to MG-63 monolayers represented approximately 80% bound specifically to the cell surface and the remainder to the surrounding extra-cellular matrix. Either co-incubation with uPA or pre-incubation with Pm resulted in increased 125I-Pg binding to osteosarcoma cells. Cell surface Pm proteolytic activity was confirmed by an amidolytic chromogenic assay. Both Pm and Pg bound to cells with Pg being activated by endogenous uPA. Plasmin activated on the cell surface was partially protected from inhibition by alpha 2-antiPm (requiring Pm lysine binding site interaction) but inhibited by aprotinin, (interacting directly with the Pm catalytic site). Resistance of cell bound Pm to alpha 2-antiPm inhibition suggests that cell surface proteolysis can occur in the presence of a soluble Pm inhibitor known to exist in the extracellular space. Based on these results, we speculate that the various bone physiological processes implicating Pm may occur at or near the bone cell surface.
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PMID:Binding and activation of plasminogen on the surface of osteosarcoma cells. 751 Nov 44

beta-Cystathionase (EC 4.4.1.8) from Bordetella avium is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the hydrolysis of L-cystine to yield pyruvic acid, NH3, and thiocysteine. The latter compound is highly toxic toward MC3T3-E1 osteogenic cells, rat osteosarcoma cells, and other cell lines maintained in tissue culture (Gentry-Weeks, C. R., Keith, J. M., and Thompson, J. (1993) J. Biol. Chem. 268, 7298-7314). Site-directed mutagenesis has established that lysine 214 of the sequence TKYVGGHSD, is primarily responsible for internal aldimine binding of PLP in the holoenzyme. Translation of the DNA sequence of the beta-cystathionase gene (metC) from B. avium, reveals 4 cysteine residues/enzyme subunit (M(r) = 42,600), and spectrophotometric analysis with 4,4'-dithiodipyridine showed that there were no disulfide linkages in the native protein. beta-Cystathionase is inhibited by sulfhydryl-reactive agents, including N-ethylmaleimide (NEM). To elucidate the mechanism of NEM inhibition, each of the 4 cysteine residues at positions 88, 117, 279, and 309 was individually replaced by alanine or glycine. The mutant proteins C88A, C117G, C279G, and C309A were purified to homogeneity, and each was assayed for enzyme activity, PLP-binding, NEM sensitivity, and susceptibility to chymotrypsin digestion. The activities of mutant proteins C88A and C279G were comparable with that of the native enzyme, and since both forms were inhibited by NEM, neither cysteine 88 nor 279 are prerequisite for enzyme activity. By elimination, cysteine residues 117 and 309 must be the targets for alkylation, and resultant inactivation of beta-cystathionase, by the -SH reactive agent. Substitution of cysteine 117 and 309 with glycine and alanine, respectively, yielded the inactive proteins C117G and C309A. PLP was not detectable in these proteins, and their absorption spectra lacked the peak (at 420 nm) that is characteristic of internal PLP-Schiff base formation. Edman degradation revealed that C117G (M(r) approximately 36,000) also lacked the first 63 amino acids comprising the N terminus of the native protein. The beta-cystathionase mutants C117G and C309A showed enhanced susceptibility to chymotrypsin digestion. Cysteine residues 117 and 309 may reside in conformationally sensitive environments, and in the native enzyme these amino acids most probably serve a structural function. Toxicity assays performed with the various mutant proteins obtained by site-directed mutagenesis established that only catalytically active forms of beta-cystathionase were were cytotoxic for tissue culture cells.
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PMID:beta-Cystathionase from Bordetella avium. Role(s) of lysine 214 and cysteine residues in activity and cytotoxicity. 770 18

The promotive effects of poly-cations on immunoglobulin production was investigated using human-human hybridoma cells. Among poly-cations tested, epsilon-poly-L-lysine with hydrochloride (approximately 4 kDa), which has been used as an antibacterial food additive, had the greatest activity in enhancing IgM production of human-human hybridoma HB4C5 cells without stimulating cell proliferation. Immunoglobulin production stimulatory (IPS) activity of epsilon-poly-lysine was not affected by trypsin digestion. It was stable below 60 degrees C but completely inactivated with heating at 100 degrees C for 30 min. epsilon-Poly-lysine also enhanced interferon-beta (IFN-beta) production of human osteosarcoma MG-63 cells, but this stimulatory effect was reduced by the trypsin digestion.
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PMID:Enhancement of production of IgM and interferon-beta in human cell lines by poly-lysine. 853 72

Monoclonal antibodies TP-1 and TP-3 are of potential utility for the radioimmunodiagnosis of osteosarcoma in both human and canine patients. The V genes of these antibodies were cloned and sequenced and to facilitate radiolabeling of these proteins, the location of the lysine residues within these sequences have been determined. The V-domains of TP-1 contain a total of 12 lysines, 10 in the framework region and 2 in the CDR region, while the V-domains of TP-3 contain a total of 14 lysines, 11 in the framework region and 3 in the CDR regions. Using space-filling models, the availability of each lysine residue for radiolabeling, and potential interference with antigen binding was predicted.
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PMID:Cloning and sequencing of V genes from anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: location of lysine residues and implications for radiolabeling. 853 37

Through the use of oligonucleotide-directed mutagenesis we have generated variants of a recombinant human parathyroid (PTH) hormone-(1-34)-homoserine (RPTH) in which a positively charged residue (Arg or Lys), a negatively charged residue (Glu), or a neutral residue (Gly) has been substituted at every position throughout the peptide. These 106 PTH analogs have been tested for their ability to stimulate cAMP production in the rat osteosarcoma cell line, UMR106. Analysis of these peptides led to the construction of several analogs containing multiple substitutions at sites of potential structural importance. Several of these analogs were shown to have 3-5-fold enhanced activity and receptor affinity. Circular dichroism (CD) and lipid binding studies were then performed on these analogs. Circular dichroism demonstrates enhanced helical content in the presence of lipid vesicles, particularly anionic lipid. The [Arg15,19,22,Lys29]RPTH (+6RPTH) analog requires higher concentrations of trifluoroethanol to attain enhanced helicity. The intrinsic tryptophan fluorescence of the peptides are blue shifted more in the presence of the anionic lipid dimyristoyl phosphatidylglycerol (DMPG) than with the zwitterionic lipid dimyristoyl phosphatidylcholine (DMPC). Effects of the peptides on the phase transition behavior of DMPC shows that +6RPTH has less effect on the lipid than does RPTH. This difference in lipid interaction is also exhibited with isothermal titration calorimetry, in which RPTH reacts exothermally with DMPG, while +6RPTH shows little or no heat change. The pH dependence of binding of the hydrophobic probe 1,1'-bis(4-anilino)-naphthalene-5,5'-trisulfonic acid, also shows a difference in exposure of hydrophobic sites between RPTH and +6RPTH. The +6RPTH has about a 5-fold greater affinity for receptor binding. We suggest that this enhanced activity is a consequence of the altered lipid interaction of +6RPTH, combined with increased conformational flexibility, particularly in the carboxyl-terminal region of the molecule.
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PMID:Conformational studies on analogs of recombinant parathyroid hormone and their interactions with phospholipids. 866 72

The metabolic control of respiration is still poorly understood, due mainly to the lack of suitable approaches for studying it in vivo. Experiments on isolated mammalian mitochondria have indicated that a relatively small fraction of each of several components of the electron transport chain is sufficient to sustain a normal O2 consumption rate. These experiments, however, may not reflect accurately the in vivo situation, due to the lack in the mitochondrial fraction of essential cytosolic components and to the use of excess of substrates in the in vitro assays. An approach is described here whereby the control of respiration by cytochrome c oxidase (COX; EC 1.9.3.1) was analyzed in intact cultured human osteosarcoma 143B.TK- cells and other wild-type cells and in mitochondrial DNA mutation-carrying human cell lines. Surprisingly, in wild-type cells, only a slightly higher COX capacity was detected than required to support the endogenous respiration rate, pointing to a tighter in vivo control of respiration by COX than generally assumed. Cell lines carrying the MERRF mitochondrial tRNA(Lys) gene mutation, which causes a pronounced decrease in mitochondrial protein synthesis and respiration rates, revealed, in comparison, a significantly greater COX capacity relative to the residual endogenous respiration rate, and, correspondingly, a higher COX inhibition threshold above which the overall respiratory flux was affected. The observed relationship between COX respiratory threshold and relative COX capacity and the potential extension of the present analysis to other respiratory complexes have significant general implications for understanding the pathogenetic role of mutations in mtDNA-linked diseases and the tissue specificity of the mutation-associated phenotype.
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PMID:In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells. 903 24

Human Monocyte Chemotactic Protein (MCP)-2 has originally been isolated from stimulated osteosarcoma cells as a chemokine coproduced with MCP-1 and MCP-3. Here, a 5'-end extended MCP-2 cDNA was cloned from a human testis cDNA library. It encoded a 76 residue MCP-2 protein, but differed from the reported bone marrow-derived MCP-2 cDNA sequence in codon 46, which coded for a Lys instead of a Gln. This MCP-2Lys46 variant, caused by a single nucleotide polymorphism (SNP), was biologically compared with MCP-2Gln46. The coding regions were subcloned into the bacterial expression vector pHEN1, and after transformation of Escherichia coli, the two MCP-2 protein variants were recovered from the periplasm. The recombinant proteins were purified to homogeneity by heparin-Sepharose affinity chromatography and reversed-phase HPLC. Edman degradation revealed a Gln residue at the NH2 terminus instead of a pGlu. To evaluate the influence of the cyclization, this Gln was chemically converted into pGlu in both MCP-2 variants. The conversion was confirmed by electrospray mass spectrometry. rMCP-2Gln46 and rMCP-2Lys46 and the NH2-terminal cyclic counterparts were tested on monocytic cells in calcium mobilization and chemotaxis assays. No significant difference in biological activity was observed between the rMCP-2Gln46 and rMCP-2Lys46 isoforms. However, for both MCP-2 variants the NH2-terminal pyroglutamate was shown to be essential for chemotaxis, but not for calcium mobilization. NH2-terminal truncation of rMCP-2Lys46 by the serine protease CD26/dipeptidyl peptidase IV (CD26/DPP IV) resulted in the cleavage of the NH2-terminal Gln-Pro dipeptide, whereas synthetic MCP-2 with an amino-terminal pGlu remained unaffected. CD26/DPP IV-clipped rMCP-2Lys46(3-76) was almost completely inactive in both chemotaxis and signaling assays. These observations indicate that the NH2-terminal pGlu in MCP-2 is necessary for chemotactic activity but also that it protects the protein against degradation by CD26/DPP IV.
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PMID:Functional comparison of two human monocyte chemotactic protein-2 isoforms, role of the amino-terminal pyroglutamic acid and processing by CD26/dipeptidyl peptidase IV. 973 Aug 40

Immunoscintigraphy is a tumour imaging technique that can have specificity, but high background radioactivity makes it difficult to obtain tumour imaging soon after the injection of radioconjugate. The aim of this study is to see whether clear tumour images can be obtained soon after injection of a radiolabelled reagent using a new linker with antibody fragments (Fab), in conditions of induced hypertension in mice. Fab fragments of a murine monoclonal antibody against human osteosarcoma were labelled with radioiodinated 3'-iodohippuryl N-epsilon-maleoyl-L-lysine (HML) and were injected intravenously to tumour-bearing mice. Angiotensin II was administered for 4 h before and for 1 h after the injection of radiolabelled Fab. Kidney uptake of 125I-labelled-HML-Fab was much lower than that of 125I-labelled-Fab radioiodinated by the chloramine-T method, and the radioactivity of tumour was increased approximately two-fold by angiotensin II treatment at 3 h after injection, indicating high tumour-to-normal tissue ratios. A clear tumour image was obtained with 131I-labelled-HML-Fab at 3 h post-injection. The use of HML as a radiolabelling reagent, combined with angiotensin II treatment, efficiently improved tumour targeting and enabled the imaging of tumours. These results suggest the feasibility of PET scan using antibody fragment labelled with 18F-fluorine substitute for radioiodine.
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PMID:A novel immunoscintigraphy technique using metabolizable linker with angiotensin II treatment. 1020 95


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