Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding of Tnp (2,4,6-trinitrophenyl) derivatives to the Fv fragment (variable region of heavy and light chains) of the mouse myeloma IgA protein MOPC 315 was investigated by 270MHz proton nuclear magnetic resonance. Two of the haptens, Tnp-glycine and Tnp-l-aspartate, are in fast exchange with the Fv fragment, and the changes in chemical shifts for both protein and hapten resonances were determined by titrations. For the tightly binding hapten epsilon-N-Tnp-alpha-N-acetyl-l-lysine, which is in slow exchange with the Fv fragment, the changes in chemical shifts for the hapten H(3)+H(5) resonances were determined by cross-saturation. By using these data and the known structure of the combining site of protein MOPC 315 [Dwek, Wain-Hobson, Dower, Gettins, Sutton, Perkins & Givol (1977), Nature (London) 266, 31-37] the mode of binding of Tnp derivatives is deduced by ring-current calculations. The trinitrophenyl ring stacks with tryptophan-93(L) (light chain) in the ;aromatic box' formed by tryptophan-93(L), tyrosine-34(L) and phenyl-alanine-34(H) (heavy chain). Further evidence for the stacking interaction with a tryptophan residue is provided by the similarity of the optical-difference spectra observed with Tnp-aminomethylphosphonate in the presence of either the Fab fragment (light chain and N-terminal half of heavy chain) of protein MOPC 315 or tryptophan. These data show that the modes of binding of all the Tnp derivatives are very similar, despite a 100-fold range in their affinities. It is also concluded that the modes of binding of Dnp (2,4-dinitrophenyl) and Tnp derivatives to protein MOPC 315 are very similar, and that the structural basis for this is that the aromatic box is large enought to allow the trinitrophenyl ring to stack with tryptophan-93(L) while still forming hydrogen bonds to asparagine-36(L) and tyrosine-34(L).
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PMID:The binding of 2,4,6-trinitrophenyl derivatives to the mouse myeloma immunoglobulin A protein MOPC 315. 62 44

The relation between structure and specificity of antibodies has been explored by 19F NMR studies of the binding of trifluoromethyl analogues of nitrophenyl haptens to the three mouse myeloma immunoglobulins M315, M460, and X25. We have used haptens with trifluoromethyl groups located at the ortho or para positions of the phenyl ring or attached to the side chain, two atoms removed from the ring (i.e.,-NHCH2CF3). The changes in chemical shift between hapten free in solution and bound to antibody are sensitive to microenvironment and range from 1.7-ppm downfield to 1-ppm upfield. The shifts of p-trifluoromethylnitrophenyl haptens bound to M315 and M460 are both large downfield shifts, which are likely caused by van der Waals interaction and ring-current effects, particularly from tyrosine-34(L); these haptens do not show similar shifts when bound to X25 which has a deletion of tyrosine34(L). Other differences in the binding of the aromatic rings of haptens by M315, M460, and X25 are observed and their origins considered. The importance of hydrogen bonding in the thermodynamic affinity of antibody for hapten has been estimated by comparisons of binding affinities for haptens with trifluoromethyl groups in place of nitro groups.
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PMID:Relation between structure and specificity of antibodies: nuclear magnetic resonance study of binding fluorine-19 labeled nitrophenyl haptens to myeloma immunoglobulins M315, M460, and X25. 69 4

Magnetic-resonance techniques are used to refine the model of the combining site of the Fv fragment of the dinitrophenyl-binding mouse myeloma protein MOPC 315 constructed by Padlan, Davies, Pecht, Givol & Wright (1976) (Cold Spring Harbor Symp. Quant. Biol.41, in the press). Light-absorption studies indicate a dinitrophenyl-tryptophan interaction in the Fv fragment of the type occurring in free solution. The Dnp-aspartate-tryptophan complex is therefore used as a starting point for the n.m.r. (nuclear-magnetic-resonance) analysis of the dinitrophenyl-Fv fragment interaction. Ring-current calculations are used to determine the geometry of the complex. The specificity of complex-formation between dinitrophenyl and tryptophan is confirmed by the lack of ring-current shifts of the dinitrophenyl resonances when tryptophan is replaced by any other aromatic amino acid. Proton n.m.r. difference spectra (at 270MHz), resulting from the addition of a variety of haptens to the Fv fragment, show that the combining site is highly aromatic in nature. Calculations on the basis of ring-current shifts define the geometry of the combining site, which involves a dinitrophenyl ring in van der Waals contact with four aromatic amino acid residues on the protein. The observation of a nuclear Overhauser effect on the H((3)) resonance of the dinitrophenyl ring provides additional constraints on the relative geometry of the H((3)) proton and an aromatic amino acid residue on the Fv fragment. The specificity of the Fv fragment for dinitrophenyl ligands arises from a stacking interaction of the dinitrophenyl ring with tryptophan-93(L), in an ;aromatic box' of essentially tryptophan-93(L), phenylalanine-34(H) and tyrosine-34(L); asparagine-36(L) and tyrosine-34(L) also contribute by forming hydrogen bonds with the nitro groups on the dinitrophenyl ring. The n.m.r. results also confirm that the antibody-hapten reaction may be visualized as a single encounter step. An Appendix shows the method of calculation of ring currents for the four aromatic amino acids and their use in calculating structures.
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PMID:The combining site of the dinitrophenyl-binding immunoglobulin A myeloma protein MOPC 315. 92 44

Anti-bilirubin-IX alpha monoclonal antibodies exclusively specific for unconjugated bilirubin-IX alpha are prepared and characterized. Using modified MBS (metamaleimidobenzoyl-N-hydroxysuccinimide ester) method, bilirubin-IX alpha was covalently coupled to bovine serum albumin (BSA) retaining its intramolecular hydrogen bonds as well as three-dimensional structure. Somatic cell fusion was performed between murine spleen cells immunized with the bilirubin-IX alpha-BSA and murine myeloma P3-X63-Ag8-U1 cells. After screening assay, 58 clones were identified which were producing antibodies not to albumin nor MBS, but to haptenic bilirubin-IX alpha. In inhibition analysis, the antibodies in the culture supernatant reacted only with bilirubin-IX alpha to a varying degree, but did not react with conjugated bilirubin-IX alpha, including bilirubin-IX alpha monoglucuronide, bilirubin-IX alpha diglucuronide, and ditauronic bilirubin-IX alpha.
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PMID:Anti-bilirubin monoclonal antibody. III. Preparation and properties of monoclonal antibodies to unconjugated bilirubin-IX alpha. 201 77

A monoclonal antibody against rat neutrophils, RP-1, was produced by hybridizing a mouse myeloma (P3-X63-Ag8.653) with BALB/c mouse spleen cells sensitized with peritoneal neutrophils from Wistar-King-Aptakeman/Hok rats. RP-1 specifically reacted to neutrophils and bone marrow cells from rats of various strains. The expression of an antigen reactive to RP-1 on rat peritoneal neutrophils was enhanced by stimulation with phorbol myristate acetate and concanavalin A. The experimental result that the expression of an antigen reactive with another anti-neutrophil monoclonal antibody was not enhanced by stimulation with phorbol myristate acetate indicates that the antibody-binding capacity of stimulated neutrophils was not nonspecifically enhanced. The enhancement of antigen expression was temperature dependent. A glycolytic inhibitor, 2-deoxy-D-glucose, and an inhibitor of intracellular calcium mobilization, 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester hydrochloride, which inhibited hydrogen peroxide release from stimulated neutrophils, did not inhibit enhancement of the expression of an antigen reactive with RP-1.
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PMID:Enhancement of the expression of a rat neutrophil-specific cell surface antigen by activation with phorbol myristate acetate and concanavalin A. 242 75

Synthetic deoxyfluoro derivatives of methyl alpha-D-glucopyranoside, as well as methyl alpha-glycosides of isomalto-oligosaccharides, some having fluorine substituted for hydroxyl groups at selected positions, have been evaluated for their binding with a myeloma monoclonal IgA known to bind only to an oligosaccharide sequence at the nonreducing end of alpha-(1----6)-linked D-glucopyranans (dextrans). The results are compatible with the antibody's possessing one subsite of high affinity for its D-glucosyl group, the remaining three subsites having low affinities for their respective D-glucosyl residues. The high-affinity antibody-subsite occurs at the interior end of the sequence of four subsites, appears to be relatively accessible, and binds the (terminal) nonreducing D-glucosyl group of the oligosaccharidic determinant using two, and possibly three, hydroxyl groups in hydrogen bonding.
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PMID:The subsites of monoclonal anti-dextran IgA W3129. 247 84

Eosinophils like neutrophils possess an oxidative metabolism which is activated by phagocytosis and cell membrane activation. Since eosinophils may take part in inflammatory reactions by releasing oxygen species and have membrane receptors for immunoglobulins, immune complexes may activate their respiratory burst. We compared the ability of phorbol myristate acetate (PMA) and immunoglobulin G (IgG) and immunoglobulin E (IgE) immune complexes to stimulate hydrogen peroxide (H2O2) release from circulating eosinophils and neutrophils. PMA was able to stimulate a significant respiratory burst in both cell types, PMA-induced H2O2 production being higher in eosinophils than in neutrophils (p less than 0.05). Similar results were obtained when the cells were stimulated by IgG (p less than 0.05). In contrast, aggregated human myeloma IgE induced a detectable H2O2 release only from peripheral blood eosinophils. We conclude that H2O2 release from eosinophils may play a role in parenchymal injury associated with hypereosinophilic disorders and the presence of immune complexes at sites of disease activity.
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PMID:Oxidative metabolism of human peripheral blood eosinophils and neutrophils: H2O2 production after stimulation with phorbol myristate acetate and immune complexes. 280 4

Idarubicin (IDA) is an anthracycline analog which differs from the parent compound by the substitution of a C4 methoxyl group with an hydrogen atom in the aglycone moiety. This drug has shown greater potency and activity in experimental and human leukemias and lymphomas by intravenous and oral routes of administration together with less cardiotoxicity than doxorubicin (DX) and daunorubicin (DNR). We have treated 15 patients with advanced multiple myeloma (MM) refractory or relapsed to standard chemotherapy regimens. The treatment schedule consisted of idarubicin 40 mg/m2 orally on day 1 every 3 weeks for 6-8 months. We obtained 8/14 partial response, 4/14 minor response and 2 progressions. One patient was not evaluable for the response because of liver toxicity not related to IDA administration. The median duration of response was 8 months with a minimum of 2 and a maximum of 12 months. Hematologic toxicity occurred in about 20% of patients and no treatment was delayed. Cardiotoxicity, defined as impairement of left ventricular ejection fraction (LVEF), was observed in one case. The major systemic toxicity observed was nausea in 80% of patients and vomiting in 40%. Hair loss resulting was socially acceptable. These results indicate that IDA is useful as a single agent, easy to administer, not cross resistant with DX and recommended for a combination regimen.
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PMID:A phase II study of idarubicin (4-demethoxydaunorubicin) in advanced myeloma. 316 69

The structure of the Fab' fragment of a human myeloma immunoglobulin was determined by x-ray crystallographic analysis at 2.8-A resolution. The Fourier map of the electron density was correlated with the aminoacid sequence to obtain a three-dimensional model. Four globular subunits, which correspond to the homology regions of the light and heavy chains, are arranged in a tetrahedral configuration. These subunits closely resemble each other, sharing a basic pattern of polypeptide chain folding. In each subunit, long sequences of tightly packed, hydrogen bonded polypeptide chain run parallel to the major axis of the subunit. No helical conformation can be seen. Different patterns of interchain disulfide linkage and unusual intrachain disulfide bonds that have been observed in other immunoglobulins can be explained with this model. The regions of hypervariable sequences in the light and heavy chains occur at one end of the molecule, in close spatial proximity.
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PMID:Three-dimensional structure of the Fab' fragment of a human immunoglobulin at 2,8-A resolution. 451 24

Cloned hybrid cells, selected for their ability to secret an IgG 2a immunoglobulin specific for single-stranded (ss) nucleic acids, were obtained by fusion of spleen cells from an unimmunized autoimmune MRL/1 pr male mouse with nonsecreting myeloma cells (MOPC-21, line Sp2/0-Ag 14). Designated MRss-1, this monoclonal antibody was (i) propagated by intraperitoneal injection of hybrid cells to pristane-treated. Balb/c mice, (ii) purified from the bulk of other proteins in ascites extracts by chromatography with DEAE-Sephacel adsorbent, and (iii) radiochemically labeled via reductive methylation using NaB3H4 and formaldehyde. The binding of 3H-labeled antibody to immobilized ssDNA- agarose, calf thymus) or soluble (fd DNA) ssDNA was rapid and dependent upon ssDNA and ionic strength, but not hydrogen ion concentration. Optimal binding occurred in both low and intermediate salt concentration (0.1-0.25 M NaCl), yet was completely abolished above 0.30 M NaCl. The presence of guanine (Gua)-containing mono-, oligo-, and polynucleotides also abolished and/or decreased 3H-labeled antibody binding to ssDNA-agarose. In these competition assays, the amount of Gua-containing mono-and oligonucleotides required to inhibit antibody binding by 50% (0.2-1.0 mg/mL) exceeded those of poly(G), rRNA, and fd DNA (i.e., 0.03-0.1 microgram/mL) by 4 orders of magnitude. In contrast, (deoxy)ribose 5'-phosphate as well as other nucleic acid derivatives devoid of Gua failed to inhibit antibody binding. The above findings were substantiated by the observation that 3H-labeled antibody bound to guanosine (G)- and guanidylate (pG)-conjugated Sepharose, yet not to other nucleoside (A, C, and U)- or nucleotide (pA, pC, and pU)-conjugated adsorbents. Last, the introduction of the methyl group at the N-2, O-6, and N-7 positions in the Gua ring system completely abolished antibody binding. Collectively, these results demonstrate that the MRss-1 antibody recognized single-stranded nucleic acid substrates by virtue of their content of guanidylate residues and, more specificity, by the presence of the Gua base moiety.
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PMID:Antibody-nucleic acid complexes. Identification of antigenic determinant of a murine monoclonal antibody specific for single-stranded nucleic acids. 617 38


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