[Long-term combination therapy of chronic polyarthritis: methotrexate and parenteral gold].
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Activities of Daily Living↗
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Monomaleimidogold labeling of the gamma subunit of the Escherichia coli F1 ATPase examined by cryoelectron microscopy.
A novel approach for locating sites of interest in a protein complex has been developed using monomaleimidonanogold (MMN). The Escherichia coli F1 ATPase, when prepared without the delta subunit, contains only a single reactive cysteine on one of the three copies of the alpha subunit. This site was reacted with MMN and the gold cluster visualized on the protein complex by cryoelectron microscopy. Additional sites for modification with MMN were added by introducing cysteine residues through site-directed mutagenesis. Labeling of two mutants, gamma S8-C and gamma T106-C, in which Ser8 and Thr106, respectively, had been replaced by a cysteine, placed the gold cluster on the central mass that is seen in the hexagonal projection of the ECF1 complex. The results establish that the central mass contains the N-terminal part of the gamma subunit.
Electrophoresis, Polyacrylamide Gel↗
Cellular and molecular pharmacology of auranofin and related gold complexes.
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Albumins↗
The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. I. Characterization of triethylphosphine gold chloride-induced biochemical and morphological changes in isolated hepatocytes.
Triethylphosphine gold complexes are effective therapeutic agents used for the treatment of rheumatoid arthritis. Many of those molecules are also highly cytotoxic in vitro and can inhibit DNA and protein synthesis. Preliminary experiments have indicated that triethylphosphine gold chloride (TEPAu) may induce the peroxidative decomposition of cellular membrane lipids. The purpose of these investigations therefore was to evaluate the role of lipid peroxidation in the mechanism of acute cytotoxicity of a gold(I) coordination complex, TEPAu, and to examine the early morphological and biochemical changes induced by TEPAu in suspensions of freshly isolated rat hepatocytes. TEPAu caused a rapid loss of cell viability at concentrations above 25 microM which was significantly different from that of control by 60 min and complete by 180 min of incubation. TEPAu also depleted cells of reduced glutathione (GSH) and increased the formation of malondialdehyde (MDA) by 60 min. Incubation of cells with either of the antioxidants, N,N'-diphenyl-p-phenylenediamine (DPPD) or promethazine blocked the formation of MDA but did not alter the time course of cell death or GSH depletion induced by TEPAu. TEPAu also caused a decrease in cellular NADPH and NADH by 10 min. Electron microscopy of hepatocytes exposed to TEPAu revealed early (5 min) formation of flocculent electron-dense precipitates within condensed mitochondria. These changes characteristically preceded cell death. Energy-dispersive electron-probe microanalysis indicated that the electron-dense precipitates did not contain detectable amounts of gold. TEPAu also caused a concentration-dependent decrease in cellular ATP and oxygen consumption in isolated rat hepatocytes. These data suggest that lipid peroxidation, as indicated by the formation of MDA, is probably not a major mechanism by which triethylphosphine gold complexes lethally injure cells. These data, therefore, suggest that mitochondria may be target organelles in TEPAu-induced toxicity to isolated rat hepatocytes.
Animals↗
In vivo and in vitro cardiotoxicity of a gold-containing antineoplastic drug candidate in the rabbit.
Bis[1,2-bis(diphenylphosphino)ethane] gold(I) chloride (Au(DPPE)+2), a cytotoxic antineoplastic drug candidate, was cardiotoxic in rabbits. Intravenous administration of Au(DPPE)+2 (15 mg/kg) as a single dose produced multiple, 2- to 5-mm subendocardial and myocardial lesions, macroscopically appearing as pale tan foci. Histologically, these lesions consisted of widely scattered zones of myocardial cell necrosis and mineralization. The myocardium also contained multifocal areas of contraction band necrosis in which aggregated clumps of disorganized myofilaments were contiguous with areas of sarcoplasm which were relatively devoid of myofilaments. In a series of in vitro studies, electron microscopic examination of isolated rabbit myocytes treated with 30 microM Au(DPPE)+2 for 15 min showed evidence of mitochondrial swelling and electron translucent mitochondrial matrices. After 60 min of incubation, myocytes had mitochondria that were condensed and disrupted but the cristae had retained their tubular profiles. Isolated rabbit myocytes exposed to 30 microM Au(DPPE)+2 had significant increases in the leakage of lactate dehydrogenase, an index of cell death. Cellular ATP content in myocytes exposed to 30 microM Au(DPPE)+2 was significantly reduced by 30 min. State 4 respiration in isolated rabbit mitochondria was significantly increased by Au(DPPE)+2 (30 microM) while state 3 respiration was unaffected. Au(DPPE)+2 also caused a rapid dissipation of the mitochondrial inner membrane electrochemical potential in a concentration-dependent manner and was accompanied by a ruthenium red-sensitive calcium efflux. These data suggest that disruption of mitochondrial function, leading to uncoupling of oxidative phosphorylation, decreased ATP synthesis, and altered mitochondrial calcium homeostasis, may be a contributing factor leading to cardiac myofibril necrosis produced by Au(DPPE)+2.
Adenosine Triphosphate↗
Elevated antigalactosyl antibody titers reflect renal injury after gold or D-penicillamine in rheumatoid arthritis.
Titers of circulating antigalactosyl antibodies (a-Gal Ab) were assessed by passive hemagglutination using rabbit red blood cells in 40 normal subjects, in 14 patients with immunodeficient states, in 47 patients with active rheumatoid arthritis (RA), and in 15 patients with an Henoch-Schönlein disease (HS). Titers of controls ranged from 1:16 to 1:64. All immunodeficient patients exhibited very low titers (1:1). On the contrary, the existence of an enhanced humoral immune response status, as observed in RA, was not reflected by a parallel increase of a-Gal Ab titers. However, in this disease, a strong relationship existed between titers exceeding control values (greater than 1:64) and the prior occurrence of renal injury under gold or D-penicillamine therapy. Lastly, the discovery of elevated titers (greater than 1:64) in HS only when renal involvement occurred further suggests that such antibodies reflect a renal injury.
Acquired Immunodeficiency Syndrome↗
Absorption and circular dichroism studies of a gold (I)-DNA complex.
The DNA binding properties of the Au(I)-containing antiarthritic drug Ridaura and related Au(I) complexes have been investigated. Absorption and circular dichroism spectroscopy show that if the gold ion possesses an easily displaced ligand, e.g., Cl- or Br-, Au(I) is capable of interacting, in a nondenaturing fashion, with calf thymus DNA. Absorption studies with the four DNA nucleosides suggest that guanine and cytosine bases are important in the Au(I)DNA interaction.
Animals↗
Undecagold clusters for site-specific labeling of biological macromolecules: simplified preparation and model applications.
We report simple and rapid procedures for the synthesis of a variety of stable, water-soluble undecagold cluster, and model applications of a thiol-reactive gold cluster for the specific labeling of cysteine residues in proteins.
Animals↗
Reactions of triethylphosphine gold(I) complexes with heme proteins: novel spin-state changes in cytochrome b562, myoglobin, and hemoglobin.
Reactions of bacterial Fe(III) cyt b562, HbO2, met Hb and met Mb with Et3PAuCl and Et3PAuNO3 (and some related complexes) have been investigated by electronic absorption and EPR and NMR spectroscopy. Except for met Hb, which denatured, the products were novel high-spin Fe(III) heme proteins. The reactions of cyt b562 and Mb were reversible. Two distinct kinetic steps were observed in the autoxidation of HbO2 and MbO2. These may involve the liberation of superoxide. Autoxidation of HbO2 occurred more rapidly than that of MbO2. The kinetics of the spin-state change of cyt b562 were too fast to measure by conventional (spectrophotometric) methods. The reaction of Et3PAuCl with HbO2 was not blocked by N-ethylmaleimide. The reactions are discussed in terms of attack by Et3PAu+ on histidine residues in the hydrophobic haem pockets of the proteins.
Animals↗
Interaction of the antitumor Au(I) complex [Au(Ph2P(CH2)2PPh2)2]Cl with human blood plasma, red cells, and lipoproteins: 31P and 1H NMR studies.
The bis-chelated tetrahedral gold(I) complex [Au(dppe)2]Cl, where dppe is Ph2P(CH2)2PPh2, is active in several animal tumor models. When added to human blood plasma in vitro it appears to bind to lipoproteins, giving a slightly broadened 31P NMR signal, and 1H NMR resonances which are too broad to detect. Some lipoprotein is denatured. 31P NMR studies suggest that some [Au(dppe)2]+ is transferred from plasma to red cells with a half-life of ca. 2 hr. The complex binds within red cell membranes and the 1H resonances of intracellular glutathione are unaffected. The 31P NMR resonance from [Au(dppe)2]+ in red cell membranes is observable only when the complex is mobilized by addition of sodium dodecyl sulphate, which also mobilizes membrane phospholipids.
Antineoplastic Agents↗
Synthesis of a radioactive labeled undecagoldcluster for application in X-ray structure analysis of ribosomes.
In order to quantitate and to determine the extent of binding of a heavy atom derivative to ribosomal particles and other components of protein biosynthesis, we prepared a 14C-radioactive labeled monofunctional undecagoldcluster. This cluster can be bound either to exposed sulfhydryl groups at the surface of the ribosomes and its subunits, or to high nucleophilic amino groups of nucleic acids as well as to proteins.
Carbon Radioisotopes↗
Localization of a specific nucleotide in yeast tRNA by scanning transmission electron microscopy using an undecagold cluster.
Scanning transmission electron microscopic images of transfer RNAs reveal the molecular dimensions and compact morphology of these small macromolecules in unprecedented detail. Selective labeling of a sulfhydryl group on 2-thiocytidine enzymatically inserted at position 75 at the 3' end of yeast tRNA(Phe) with an undecagold cluster permits identification of this specific tRNA site by dark field STEM. Imaging of a single nucleotide at a defined location on the tRNA molecule should make it possible to localize in situ tRNAs at the A, P, and E sites of the ribosomal peptidyl transferase center, and in complexes of tRNA with enzymes and elongation factors. In addition, this approach may be used for the highly specific topographical mapping of other RNAs and/or biological macromolecular complexes.
Gold↗
Mitochondria are primary targets in apoptosis induced by the mixed phosphine gold species chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I) in melanoma cell lines.
Based on previous evidence indicating a selective cytotoxic activity of the mixed phosphine gold complex chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I) for melanoma cells, we investigated the cellular bases of its antiproliferative effect in a panel of human melanoma cell lines (JR8, SK-Mel-5, Mel-501, 2/60, 2/21 and GRIG). The drug consistently induced a dose-dependent inhibition of cell growth, with IC50 values ranging from 0.8 to 2.3 microM and, when tested under the same experimental conditions, its cytotoxic activity was higher than (from 2- to 5-fold) or comparable to that of cisplatin as a function of cell lines. The ability of the gold complex to activate programmed cell death was assessed in JR8 and 2/60 cells, and a dose-dependent increase in cells with an apoptotic nuclear morphology was observed in both cell lines (up to 40 and 66% of the overall cell population, for JR8 and 2/60 cell lines, respectively). Such an apoptotic response was mediated by a dose-dependent loss of mitochondrial membrane potential, cytochrome c and Smac/DIABLO release from mitochondria into cytosol and enhanced caspase-9 and caspase-3 catalytic activity. A reduced or completely abrogated expression of the anti-apoptotic proteins c-IAP1, XIAP and survivin in drug-treated cells was also observed. Overall, results from the study indicate that chlorotriphenylphosphine-1,3-bis(diphenylphosphino)propanegold(I) markedly inhibits melanoma cell growth by inducing mitochondria-mediated apoptosis and suggest it as a good candidate for additional evaluation as an anticancer agent against melanoma.
Antineoplastic Agents↗
Medication use, tamoxifen (TAM), and TAM metabolite concentrations in women with breast cancer.
Tamoxifen (TAM) is commonly used as an adjuvant treatment for breast cancer. Although patients taking TAM are often taking medications for comorbidities, data regarding the interaction of TAM with other medications are limited. Thus, this study was carried out to determine whether medications co-prescribed with TAM significantly influence the plasma concentrations of TAM and its metabolites (N-desmethyltamoxifen; N-DMT and 4-hydroxytamoxifen; 4-OHT) in 98 women diagnosed with breast cancer. Participants taking diuretics had significantly higher plasma concentrations of TAM and N-DMT than participants not taking a diuretic. Arthritis/pain medication intake was negatively associated with plasma TAM concentrations. Chemotherapeutic agents, allergy drugs, anti-depressants, and diabetes medications did not significantly alter plasma TAM or metabolite concentrations. This suggests that diuretic or an arthritis/pain medication may affect TAM metabolism.
Anti-Allergic Agents↗
Combined genetic and chemical capsid modifications enable flexible and efficient de- and retargeting of adenovirus vectors.
Numerous attempts to target viral gene therapy vectors to specific cells have met with limited success. Here we describe a novel virus vector-targeting platform based on a unique combination of genetic and chemical vector particle modifications to overcome typical restrictions in virus vector targeting. We genetically introduced cysteines at solvent-exposed positions of the adenovirus capsid. The corresponding thiol groups were highly reactive, and we established procedures for controlled covalent coupling to them of protein and nonprotein ligands. After the coupling of transferrin, the particles were efficiently targeted to the transferrin receptor pathway. Depending on the chemistry used, ligands could be coupled under the formation of thioether or disulfide bonds, the latter allowing for separation of ligand and particle after cell entry in the endosome. Furthermore, this technology could be efficiently combined with vector shielding for true retargeting: after amino-PEGylation of the vector particles the genetically introduced thiols were still accessible for ligand coupling, and particles could be retargeted to the transferrin receptor. Since this platform is robust, can be scaled, is compatible with industrial standards, and can integrate chemically diverse molecules as ligands, it may be used for clinical gene therapy and, potentially, also for vaccination.
Adenoviridae↗
Inhibition of human neutrophil collagenase by gold(I) salts used in chrysotherapy.
Six gold(I) salts, some of which are used as drugs in chrysotherapy, are shown to be inhibitors of two forms of human neutrophil collagenase. The IC50 values vary over six orders of magnitude, the lowest being 3.5 nM for Myocrisin. Thus, inhibition is greatly affected by the identity of the ligands to the gold(I) atom. The inhibition of collagenase by these gold(I) salts may be a partial basis for their antiarthritic action.
Arthritis, Rheumatoid↗
Phosphorylation of anticancer nucleoside analogs by human mitochondrial deoxyguanosine kinase.
The kinetic properties of recombinant human mitochondrial deoxyguanosine kinase (dGK, EC 2.7.1.113) for 2'-deoxyguanosine and the clinically important nucleoside analogs 2-chloro-2'-deoxyadenosine (CdA), 9-beta-D-arabinofuranosylguanine (araG) and 2',2',-difluorodeoxyguanosine (dFdG) were determined. The Michaelis-Menten kinetic parameters, comparing ATP and UTP as phosphate donors, demonstrated a marked increase in phosphorylation efficiency (VmaxKm) with UTP in comparison with ATP for both CdA and araG. The difluoro analog dFdG was an efficient substrate for recombinant dGK with an apparent Km of 16 microM with ATP as phosphate donor. We compared the kinetic properties of dGK with those of the related enzyme deoxycytidine kinase (dCK, EC 2.7.1.74). Although the purines 2'-deoxyguanosine (dGuo) and 2'-deoxyadenosine are substrates for both dGK and dCK, only CdA among the purine nucleoside analogs tested was an efficient substrate for both dCK and dGK. In competition with dGuo, the most efficient analog for phosphorylation by dGK was araG, as indicated by a lower Ki value than for CdA and dFdG. Of the purine analogs tested as substrates for dCK, only CdA could compete with 2'-deoxycytidine (dCyd). No inhibition of dCK-mediated dCyd phosphorylation was found by either araG or dFdG. In crude cell extract of HeLa and Capan 2 cells, the major CdA phosphorylation was contributed by dCK, while most araG phosphorylation was a result of dGK activity. Our study with pure recombinant enzymes confirms that dGK is mainly responsible for araG and dFdG phosphorylation, whereas dCK is the most important enzyme for activation of CdA and 2',2'-difluorodeoxycytidine (dFdC).
Antineoplastic Agents↗
Localization of calmodulin binding sites on the ryanodine receptor from skeletal muscle by electron microscopy.
Calmodulin (CaM) is a regulator of the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum of skeletal and cardiac muscle. The locations where CaM binds on the surface of the skeletal muscle ryanodine receptor were determined by electron microscopy. Wheat germ CaM was labeled specifically at Cys-27 with a maleimide derivative of a 1.4-nm-diameter gold cluster, and the gold-cluster-labeled CaM was bound to the purified ryanodine receptor. The complexes were imaged in the frozen-hydrated state by cryoelectron microscopy with no stains or fixatives present. In the micrographs, gold clusters were frequently observed near the corners of the square-shaped images of the ryanodine receptors. In some images, all four corners of the receptor were occupied by gold clusters. Image averaging allowed the site of CaM binding to be determined in two dimensions with an estimated precision of 4 nm. No changes were apparent in the quaternary structure of the ryanodine receptor upon binding CaM to the resolution attained, about 3 nm. Side views of the ryanodine receptor, in which the receptor is oriented approximately perpendicular to the much more frequent fourfold symmetric views, were occasionally observed, and showed that the CaM binding site is most likely on the surface of the receptor that faces the cytoplasm. We conclude that the CaM binding site is at least 10 nm from the transmembrane channel of the receptor and, consequently, that long-range conformational changes are involved in the modulation of the calcium channel activity of the receptor by CaM.
Animals↗