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PubMed2005

90Y Labeling of monoclonal antibody MOv18 and preclinical validation for radioimmunotherapy of human ovarian carcinomas.

The monoclonal antibody (mAb) MOv18 binds the membrane alpha isoform of the folate receptor (FR) which is overexpressed in human ovarian carcinoma cells. Exploiting the targeting capacity of this mAb, we developed and preclinically validated a protocol for the stable labeling of the mAb with 90Y, an isotope which has shown promise in cancer radioimmunotherapy. MOv18 was derivatized with the stable macrocyclic ligand p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (Bz-DOTA). MOv18-Bz-DOTA conjugates were labeled with 90Y or 111In under metal-free and good laboratory practice conditions. At the optimal Bz-DOTA/mAb derivatization ratio of 4-5, conjugates maintained binding activity up to 6 months, were efficiently labeled with 90Y or 111In (mean labeling yield 85 and 64%, associated to a final mean specific activity of 74 and 37 MBq/mg) and displayed a mean immunoreactivity of 60 and 58%, respectively. The radiolabeled preparations were stable in human serum, with >97% radioactivity associated to mAb at 48 h after labeling. The ability of 90Y- and 111In-MOv18 to localize FR on tumors in vivo was analyzed in nude mice bearing tumors induced by isogenic cell lines differing only in the presence or absence of the relevant antigen [A431FR (FR-positive) and A431tMock (FR-negative)]. In vivo biodistribution in organs other than tumor was comparable in non-tumor-, A431tMock- and A431FR-bearing mice, whereas the median tumor uptake of the radiolabeled reagents, expressed as area under the curve (AUC) and maximum uptake (Umax), was significantly higher (sixfold to sevenfold) in A431FR than in A431tMock tumors (P=0.0465 and P=0.0332, respectively). Mean maximum uptake (% ID/g) for 90Y-MOv18 was 53.7 and 7.4 in A431FR and A431tMock respectively; corresponding values for 111In-Mov18 were 45.0 and 11.3. These data demonstrate the feasibility of 90Y-labeling of MOv18 without compromising antibody binding ability and the immunoreagent-specific localization in vivo on FR-expressing tumors, suggesting the suitability of 90Y-MOv18 for clinical studies.

Antibodies, Monoclonal↗

PubMed1981

Zinc metalloenzyme properties of active and latent collagenase from rabbit bone.

1. Inhibition of collagenase from rabbit bone cultures by the chelating agents 1,10-phenanthroline and EDTA is almost completely reversed by Zn2+; other metal cations are less effective in reversing the inhibition. Optimal restoration of activity is achieved at Zn2+ concentrations below that of the chelator, but excess of Zn2+ is inhibitory. 2. Prolonged incubation of collagenase with either chelator causes irreversible inactivation. This inactivation is prevented by Zn2+ at the same concentrations needed to reverse the primary inhibition. 3. Collagenase incorporates 65Zn by exchange when incubated with 1,10-phenanthroline and Zn2+ containing this radioactive isotope. The 65Zn2+ can be removed from its binding site in collagenase by 1,10-phenanthroline or EDTA. Irreversible inactivation of collagenase by chelators destroys its ability to incorporate 65Zn2+. 4. Latent collagenase, the inhibited form in which collagenase first appears in culture, behaves similarly to the active enzyme in 65Zn2+-exchange experiments, but is resistant to irreversible inactivation by chelators. 5. It is concluded that collagenase is a zinc metalloenzyme that forms an inactive and unstable apoenzyme on treatment with chelators. The bound inhibitor component of latent collagenase evidently stabilizes the apoenzyme.

Animals↗

PubMedDate not supplied

Synthesis and biological evaluation of a new type of 99mtechnetium-labeled Fatty Acid for myocardial metabolism imaging.

Technetium-labeled fatty acids intended for myocardial metabolism imaging and the respective rhenium model complexes were synthesized according to the "4 + 1" mixed-ligand approach and investigated in vitro and in vivo. The non-radioactive rhenium model complexes were characterized by NMR, IR, and EA, and the geometrical impact of the chelate unit on the integrity of the fatty acid head structure was determined by single-crystal X-ray analyses. To estimate the diagnostic value of the 99mTc-labeled fatty acids, the compounds were investigated in experiments in vitro and in biodistribution studies using male Wistar rats. The new fatty acid tracers contain the metal core in the oxidation states +3, well-wrapped in a trigonal-bipyramidal coordination moiety, which is attached at the omega-position of a fatty acid chain. This structural feature is considered to be a good imitation of the well-established iodinated phenyl fatty acids. High heart extraction in perfused heart studies (up to 26% injected dose (ID)) and noticeable heart uptake of the 99mTc tracers in vivo being in the order of 2% ID/g at 5 min (postinjection, pi.), accompanied by a good heart to blood ratio of 8, confirms that the new Tc compounds are suitable as fatty acid tracers.

Animals↗

PubMed1988

Carbohydrate-linked asparagine-101 of prothrombin contains a metal ion protected acetylation site. Acetylation of this site causes loss of metal ion induced protein fluorescence change.

Prothrombin fragment 1 (prothrombin residues 1-156) contains two acetylation sites that are protected from derivatization by calcium. The first site was protected by only calcium [Welsch, D. J., & Nelsestuen, G. L. (1988) Biochemistry (second of three papers in this issue)] while the second site was protected by magnesium as well. To identify this second acetylation site, fragment 1 was first acetylated with unlabeled reagent in the presence of magnesium. Metal ions were removed, and the protein was acetylated with radiolabeled reagent. The incorporated radiolabel was stable over long periods of time and at acidic or basic pH as long as elevated temperatures were avoided. The radiolabel was removed by treatment of the protein at pH 10 and 50 degrees C or with 0.2 M hydroxylamine at 50 degrees C for at least 30 min. Proteolytic degradation of the protein showed that the radioactivity appeared in a tryptic peptide corresponding to residues 94-111 of prothrombin. The Lys-97 in this peptide was acetylated but did not contain radiolabel. Amino acid sequence analysis revealed that the radiolabel was associated with an unextracted sequence product. Aglycofragment 1, produced by treatment of fragment 1 with HF, was radiolabeled by this procedure; peptide 94-111 was isolated and was further digested with protease. The major radiolabeled product contained Asn101-Ser102 along with the expected chitobiose attached to Asn-101. NMR analysis revealed the presence of three acetate groups which would correspond to two from the chitobiose plus the incorporated acetate residue.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗

PubMed1985

Biliary excretion of nickel in rats.

Nickel (Ni) concentrations were determined by liquid scintillation spectrometry or electrothermal atomic absorption spectrophotometry in bile and plasma samples obtained from male rats following subcutaneous (s.c.) injection of 63NiCl2 (1.7 mumol/kg) or non-radioactive NiCl2 (125 or 250 mumol/kg). During the intervals from 1-6 or 11-16 h post-injection, the bile:plasma ratios of Ni concentrations ranged from 0.045-0.13, and the excretory clearance of Ni in bile ranged from 0.027-0.055 ml/h. The estimated biliary excretion of Ni in the 24 h post-injection amounted to less than 0.5% of the respective doses of NiCl2. Contrary to previous findings with other divalent metal ions, this study shows that biliary excretion is quantitatively unimportant for the elimination of exogenous Ni(II) in rats.

Animals↗

PubMed2003

Immobilisation of glucose oxidase within metallic nanotubes arrays for application to enzyme biosensors.

Arrays of nanoscopic gold tubes were prepared by electroless deposition of the metal within the pores of polycarbonate particle track-etched membranes (PTM). Glucose oxidase (Gox) was immobilised onto preformed self-assembled monolayers (SAMs) (mercaptoethylamine or mercaptopropionic acid) on electroless gold via cross-linking with glutaraldehyde or covalent attachment by carbodiimide coupling. The effectiveness of the different steps in the Gox immobilisation procedure was assessed by contact angle measurements, cyclic voltammetry and X-ray photoelectron spectroscopy. The enzyme loading was estimated by radioactivity measurements. The sensitivity to beta-glucose of these different biosensors has been evaluated. Glucose responses as large as 400 nA mM(-1) cm(-2) have been obtained. To our knowledge, this sensitivity value is amongst the highest values reported in the literature for comparable biosensor systems.

Biosensing Techniques↗

PubMed1987

Photoaffinity labeling of the thymidine triphosphate binding domain in Escherichia coli DNA polymerase I: identification of histidine-881 as the site of cross-linking.

Using the technique of ultraviolet-mediated cross-linking of substrate deoxynucleoside triphosphates (dNTPs) to their acceptor site [Abraham, K. I., & Modak, M. J. (1984) Biochemistry 23, 1176-1182], we have labeled the Klenow fragment of Escherichia coli DNA polymerase I (Pol I) with [alpha-32P]dTTP. Covalent cross-linking of [alpha-32P]dTTP to the Klenow fragment is shown to be at the substrate binding site by the following criteria: (a) the cross-linking reaction requires dTTP in its metal chelate form; (b) dTTP is readily competed out by other dNTPs as well as by substrate binding site directed reagents; (c) labeling with dTTP occurs at a single site as judged by peptide mapping. Under optimal conditions, a modification of approximately 20% of the enzyme was achieved. Following tryptic digestion of the [alpha-32P]dTTP-labeled Klenow fragment, reverse-phase high-performance liquid chromatography demonstrated that 80% of the radioactivity was contained within a single peptide. The amino acid composition and sequence of this peptide identified it as the peptide spanning amino acid residues 876-890 in the primary sequence of E. coli Pol I. Chymotrypsin and Staphylococcus aureus V8 protease digestion of the labeled tryptic peptide in each case yielded a single smaller fragment that was radioactive. Amino acid analysis and sequencing of these smaller peptides further narrowed the dTTP cross-linking site to within the region spanning residues 876-883. We concluded that histidine-881 is the primary attachment site for dTTP in E. coli DNA Pol I, since during amino acid sequencing analysis of all three radioactive peptides loss of the histidine residue at the expected cycle is observed.

Amino Acid Sequence↗

PubMedDate not supplied

Treatment of mice bearing a Krebs ascitic tumor by means of a protocol based on radioactive copper (64Cu). II. Analysis of the treatment.

A new treatment is proposed for mice bearing a Krebs ascitic tumor targeting on both the malignant cells and the host cells having the "cancer functioning" (cancer cells) (Anticancer Res 9: 941-946 1989). It is shown that the treatment (a) injure specifically via 64Cu transmutation the DNA of the malignant cells and further perform (with thioproline or spermine) a "reverse transformation" on the damage DNA; (b) restore a "noncancer functioning" in the host cells which had become "cancer cells"; this restoration was performed using, at physiological concentrations, natural compounds already present in all cell types such as metal ions, amino acids, vitamin D2, thyroxine and chelating substances. To decrease the damage induced in the organism by the radiation emitted by 64Cu, a radioprotector, glycerol, was used. Two different strains of mice were used (Swiss or CBA). For each of them, the same treatment was efficient on condition that thioproline or spermine was used for Swiss or CBA mice respectively.

Animals↗

PubMed2004

Radionuclides-hyaluronan-conjugate thromboresistant coatings to prevent in-stent restenosis.

Catheter-based brachytherapy is one of the most effective modalities to inhibit hyperplasia following revascularization procedures. Radioactive stents have failed, however, to prevent clinical hyperplasia due to excessive late lumen loss on the edge of the devices. Numerous strategies have been proposed to circumvent the drawbacks of irradiation therapies, such as the use of more appropriate radionuclides or the "hot-end" stents approach. This paper describes versatile radioactive devices obtained by coating plasma functionalized surfaces-stents or catheters-with a hyaluronan (HA)-diethylenetriamine pentaacetic acid (DTPA) conjugate (HA-DTPA) complexed with a gamma or beta radionuclide. Yttrium and indium were used as radionuclide models, due to their suitability for endovascular radiotherapy. X-ray photoelectron microscopy and time-of-flight secondary ions mass spectrometry analyses confirmed the successful immobilization of the HA-DTPA conjugate on both the metallic (NiTi) and polymeric (Teflon) plasma functionalized surfaces. HA-DTPA-coated surfaces were significantly more hydrophilic than bare surfaces (39.5 degrees vs. 67 degrees on NiTi substrate and 29 degrees vs. 128 degrees on Teflon substrate). Therapeutic doses of yttrium and indium were easily loaded onto the surfaces and remained stable over 2 weeks with a radionuclide loss of about 6%. The HA-DTPA-coated Teflon surfaces presented significantly less fibrinogen adsorption than uncoated materials in an in vitro flow model. This approach, which combines the hemocompatibility of HA-coated surfaces and the anti-proliferative effects of an appropriate radiotherapy, constitutes a promising methodology to alleviate the restenosis induced by existing devices.

Adsorption↗

PubMed1999

Delivery of diagnostic agents for gamma-imaging.

The administration of radiolabeled compounds with gamma-emitting radionuclides allows real time pursuit of in vivo behavior of the compounds by external counting of the radioactivity. If the compounds possess a specific localization mechanism to target tissue, the image reflects the specific function of the target. This technique has widely been applied in diagnostic nuclear medicine combined with appropriate radionuclides for clinical use. Two strategies have been developed to design radiolabeled compounds for targeted imaging. One constitutes tethering radiolabeled compounds to carrier molecules that possess specific localization mechanisms to target tissue. Another approach constitutes chemical design of radiolabeled compounds, especially metallic compounds, that possess specific localization characteristics to the target per se. In this manuscript, progress of chemical design of radiolabeled compounds for targeted imaging is briefly reviewed. Emphasis is laid on chemical design of radiolabeled antibodies for targeted imaging.

Journal Article↗

PubMed2001

Why and how to avoid stenting during brachytherapy.

Intracoronary radiation is a promising therapy to reduce restenosis after percutaneous coronary intervention. It may be anticipated that radiation and intracoronary stents - the current standard coronary revascularization procedure - have a synergic antirestenosis effect. However, this potential benefit has not been proven in the clinical scenario. Indeed, this combined approach (stenting plus brachytherapy) may even be harmful. Delayed endothelialization and late stent malapposition are important drawbacks of implanting a metallic prosthesis in the setting of radiation therapy. Owing to the relatively high frequency of late thrombosis after stenting irradiated coronary arteries, the Food and Drug Administration required that the labeling of both gamma- and beta-radiation devices recently approved for clinical use explicitly advise avoidance of the placement of new stents. The pathophysiologic aspects as well as the clinical implications of the implantation of a new stent in association with radiation delivered by radioactive stents or catheter-based systems are discussed in this paper.

Journal Article↗

PubMed1991

In vitro identification of a soluble protein:geranylgeranyl transferase from rat tissues.

The gamma subunit of mammalian trimeric G proteins has been shown previously to be modified in vivo on a cysteine residue situated at the carboxyl-terminal sequence-Cys-Ala-Ile-Leu-COOH by a 20-carbon prenyl moiety geranylgeranyl (Mumby, S. M., Casey, P. J., Gilman, A. G., Gutowski, S., and Sternweis, P. C. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 5873-5877; Yamane, H. K., Farnsworth, C. C., Xie, H., Howald, W., Fung, B. K-K., Clarke, S., Gelb, M. H., and Glomset, J. A. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 5866-5872). A biotinylated peptide acceptor comprising the eight carboxyl-terminal amino acids of the gamma subunit and tritiated geranylgeranyl diphosphate were utilized to monitor a protein:prenyl transferase activity in rat organs of varying age. The transferase activity was dependent upon the presence of divalent metal ions and maximal activity was achieved with either 1 mM ZnCl2 or 20 mM MgCl2. Activity was shown to be linear with respect to time, protein concentration, substrate concentration, and the pH optimum was 7.5. Protein:geranylgeranyl transferase activity was detected in all rat organs studied with the highest specific activity in brain S100. No activity was detected in the membrane fraction. The specific activity in brain, liver, kidney, and heart increased with age. Radioactivity incorporated into the peptide acceptor from both [1-3H]geranylgeranyl diphosphate and [5-3H]mevalonate by 21-day-old rat brain S100 was released by treatment with methyl iodide, and in both cases, analysis of the cleavage products by reversed phase high performance liquid chromatography showed a peak of radioactivity co-eluting with a geranylgeraniol standard which was well resolved from a farnesol standard. This indicated that the rat brain S100 contained not only the protein:geranylgeranyl transferase but also geranylgeranyl synthetase activity and that the peptide acceptor was specific for geranylgeranyl under the conditions tested.

Age Factors↗

PubMed2003

Phosphoprotein with phosphoglycerate mutase activity from the archaeon Sulfolobus solfataricus.

When soluble extracts of the extreme acidothermophilic archaeon Sulfolobus solfataricus were incubated with [gamma-(32)P]ATP, several proteins were radiolabeled. One of the more prominent of these, which migrated with a mass of approximately 46 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), was purified by column chromatography and SDS-PAGE and subjected to amino acid sequence analysis via both the Edman technique and mass spectroscopy. The best match to the partial sequence obtained was the potential polypeptide product of open reading frame sso0417, whose DNA-derived amino acid sequence displayed many features reminiscent of the 2,3-diphosphoglycerate-independent phosphoglycerate (PGA) mutases [iPGMs]. Open reading frame sso0417 was therefore cloned, and its protein product was expressed in Escherichia coli. Assays of its catalytic capabilities revealed that the protein was a moderately effective PGA mutase that also exhibited low levels of phosphohydrolase activity. PGA mutase activity was dependent upon the presence of divalent metal ions such as Co(2+) or Mn(2+). The recombinant protein underwent autophosphorylation when incubated with either [gamma-(32)P]ATP or [gamma-(32)P]GTP. The site of phosphorylation was identified as Ser(59), which corresponds to the catalytically essential serine residue in bacterial and eucaryal iPGMs. The phosphoenzyme intermediate behaved in a chemically and kinetically competent manner. Incubation of the (32)P-labeled phosphoenzyme with 3-PGA resulted in the disappearance of radioactive phosphate and the concomitant appearance of (32)P-labeled PGA at rates comparable to those measured in steady-state assays of PGA mutase activity.

Adenosine Triphosphate↗

PubMed2006

X-ray and neutron scattering studies of the hydration structure of alkali ions in concentrated aqueous solutions.

The presence of ions in water provides a rich and varied environment in which many natural processes occur with important consequences in biology, geology and chemistry. This article will focus on the structural properties of ions in water and it will be shown how the 'difference' methods of neutron diffraction with isotopic substitution (NDIS) and anomalous X-ray diffraction (AXD) can be used to obtain direct information regarding the radial pair distribution functions of many cations and anions in solution. This information can subsequently be used to calculate coordination numbers and to determine ion-water conformation in great detail. As well as enabling comparisons to be made amongst ions in particular groups in the periodic table, such information can also be contrasted with results provided by molecular dynamics (MD) simulation techniques. To illustrate the power of these 'difference' methods, reference will be made to the alkali group of ions, all of which have been successfully investigated by the above methods, with the exception of the radioactive element francium. Additional comments will be made on how NDIS measurements are currently being combined with MD simulations to determine the structure around complex ions and molecules, many of which are common in biological systems.

Ions↗

PubMed1998

Temporal changes of 210Po in temperate coastal waters.

The temporal variation of Polonium-210 (210Po) was examined in coastal sea water, the mussel Mytilus edulis, the winkle Littorina littorea and green alga Ulva lactuca in order to investigate the entry of 210Po into the marine food chain. More than 99% of 210Po in the water column occurred in the particulate phase. Dissolved 210Po concentrations peaked during the spring phytoplankton bloom and it is suggested this is related to preferential scavenging of 210Po by the increased numbers of bacteria, viruses and small dissolved particulates. Changes in L. littorea 210Po specific activity are thought not to be related to food, but to a drop in body weight following spawning. Much of the 210Po accumulated by M. edulis was located in the digestive gland. The specific activity of 210Po in the digestive gland of M. edulis was shown to be strongly correlated with changes in sea water suspended particulate specific activity. Examination of other trace metal (Ag, Al, As, Ca, Cd, Cr, Co, Cu, Fe, Hg, K, Mg, Mn, Na, Ni, Sb, Se, Sn and Zn) variations in the digestive gland revealed that class B and borderline metals had a strong positive correlation with 210Po. On-going work is investigating whether the accumulation and loss of 210Po is affected by the presence of metallothioneins.

Animals↗

PubMedDate not supplied

New stent technologies.

Coronary stents were developed to overcome the two main limitations of balloon angioplasty, acute occlusion and long-term restenosis. Coronary stents can tack back intimal flaps and seal the dissected vessel wall, thereby treating acute or threatened vessel closure after unsuccessful balloon angioplasty. After successful balloon angioplasty, stents can prevent late vessel remodeling (chronic vessel recoil) by mechanically enforcing the vessel wall and resetting the vessel size, resulting in a low incidence of restenosis. All currently available stents are composed of metal, and the long-term effects of their implantation in the coronary arteries are still not clear. Because of the metallic surface, they are also thrombogenic; therefore, rigorous antiplatelet or anticoagulant therapy is theoretically required. Furthermore, they have an imperfect compromise between scaffolding properties and flexibility, resulting in an unfavorable interaction between stents and unstable or thrombus-laden plaque. Finally, they still induce substantial intimal hyperplasia that may result in restenosis. Future stents can be made less thrombogenic by modifying the metallic surface or coating it with an antithrombotic agent or a membrane eluting an antithrombotic drug. The unfavorable interaction with the unstable plaque and the thrombus burden can be overcome by covering the stent with a biological conduit, such as a vein, or a biodegradable material that can be endogenous, such as fibrin, or exogenous, such as a polymer. Finally, the problem of persisting induction of intimal hyperplasia may be overcome with the use of either a radioactive stent or a stent eluting an antiproliferative drug.

Coronary Angiography↗

PubMed1997

Endovascular stents: a 'break through technology', future challenges.

Coronary stents were developed to overcome the two main limitations of balloon angioplasty, acute occlusion and long term restenosis. Coronary stents can tack back intimal flaps and seal the dissected vessel wall and thereby treat acute or threatened vessel closure after unsuccessful balloon angioplasty. Following successful balloon angioplasty stents can prevent late vessel remodeling (chronic vessel recoil) by mechanically enforcing the vessel wall and resetting the vessel size resulting in a low incidence of restenosis. All currently available stents are composed of metal and the long-term effects of their implantation in the coronary arteries are still not clear. Because of the metallic surface they are also thrombogenic, therefore rigorous antiplatelet or anticoagulant therapy is theoretically required. Furthermore, they have an imperfect compromise between scaffolding properties and flexibility, resulting in an unfavourable interaction between stents and unstable or thrombus laded plaque. Finally, they still induce substantial intimal hyperplasia which may result in restenosis. Future stent can be made less thrombogenic by modifying the metallic surface, or coating it with an antithrombotic agent or a membrane eluting an antithrombotic drug. The unfavourable interaction with the unstable plaque and the thrombus burden can be overcome by covering the stent with a biological conduit such as a vein, or a biodegradable material which can be endogenous such as fibrin or exogenous such as a polymer. Finally the problem of persisting induction of intimal hyperplasia may be overcome with the use of either a radioactive stent or a stent eluting an antiproliferative drug.

Animals↗

PubMed1976

Increased attachment of nucleic acids to eukaryotic and prokaryotic cells induced by chemical and physical carcinogens and mutagens.

Significantly enhanced attachment to Ehrlich ascites and Escherichia coli cells was observed for radioactive DNA and RNA in the presence of chemical mutagens and ultimate carcinogens. In some instances, formation of nucleic acid-protein adducts by these compounds further (or similarly) enhanced the binding. DNA irradiated with ultraviolet light in the presence of a protein bound more efficiently than either an unirradiated mixture of these two macromolecules or DNA irradiated alone. The spectrum of compounds tested and found active in this system includes alkylating agents, aromatic amines, and carcinogenic metals. Precarcinogens and nonultimate carcinogenic chemicals, as well as tumor-promoting agents, did not increase the binding. However, addition of extracts from mouse or rat livers activated precarcinogenic and proximate carcinogenic chemicals and resulted in enhanced cellular attachment of indicator nucleic acids in their presence. Possible usefulness of this test system for fast and efficient screening for environmental carcinogens and mutagens, as well as possible relevance of the observed phenomena to in vivo effects of chemical and physical carcinogens, is considered.

Alkylating Agents↗