scholarly journals Fe-EDTA-Bisamide and Fe-ADR-925, The Iron-Bound Hydrolysis Product of the Cardioprotective Agent Dexrazoxane, Cleave DNA Via the Hydroxyl Radical

1997 ◽  
Vol 4 (4) ◽  
pp. 199-205 ◽  
Author(s):  
Thomas J. Magliery ◽  
Lizabeth K. Vitellaro ◽  
Ndeye Khady Diop ◽  
Rosemary A. Marusak
Keyword(s):  
Side Effects ◽  
Hydroxyl Radical ◽  
Plasmid Dna ◽  
Dna Cleavage ◽  
Antitumor Agents ◽  
Hydrolysis Product ◽  
Solution Chemistry ◽  
Radical Scavenger ◽  
Radical Production ◽  
Radical Generation

Use of the antitumor drug doxorubicin is limited by cardiomyopathic side-effects which are believed to be due to iron-mediated hydroxyl radical generation. Dexrazoxane reduces this cardiotoxicity, possibly by removal of iron from doxorubicin by the EDTA-like hydrolysis product of dexrazoxane, ADR-925. However, EDTA-diimides like dexrazoxane, previously used as antitumor agents, are themselves carcinogenic, and recent studies have found that Fe-ADR-925 can also promote hydroxyl radical production. This study demonstrates that, like Fe-EDTA, Fe-ADR-925 and a related desmethyl complex can cleave plasmid DNA under Fenton conditions, and suggests by radical scavenger study that this cleavage is probably via the hydroxyl radical. Differences in DNA cleavage dependence upon concentrations of Fe-EDTA, Fe-ADR-925 and Fe-EDTA-bisamide can be explained by differences in the solution chemistry of the complexes.

scholarly journals Hydroxyl-radical production and ethanol oxidation by liver microsomes isolated from ethanol-treated rats

1986 ◽  
Vol 233 (3) ◽  
pp. 755-761 ◽  
Author(s):  
G Ekström ◽  
T Cronholm ◽  
M Ingelman-Sundberg
Keyword(s):  
Amino Acid ◽  
Hydroxyl Radical ◽  
Ethanol Oxidation ◽  
Liver Microsomes ◽  
Radical Scavenger ◽  
Ethanol Treatment ◽  
Radical Production ◽  
Apparent Homogeneity ◽  
Nadph Oxidation ◽  
Cytochrome P 450

In order to distinguish between the mechanism of microsomal ethanol oxidation and hydroxyl-radical formation, the rate of cytochrome P-450 (P-450)-dependent oxidation of dimethyl sulphoxide (Me2SO) was determined in the presence and in the absence of iron-chelating compounds, in liver microsomes from control, ethanol- and phenobarbital-treated rats. Ethanol treatment resulted in a specific increase (3-fold) of the microsomal ethanol oxidation and NADPH consumption per nmol of P-450. A form of P-450 was purified to apparent homogeneity from the ethanol-treated rats and characterized with respect of amino acid composition and N-terminal amino acid sequence. Specific ethanol induction of a cytochrome P-450 species having a catalytic-centre activity of 20/min for ethanol and consuming 30 nmol of NADPH/min could account for the results observed with microsomes. Phenobarbital treatment caused 50% decrease in the rate of ethanol oxidation and NADPH oxidation per nmol of P-450. The rate of oxidation of the hydroxyl-radical scavenger Me2SO was increased 3-fold by ethanol or phenobarbital treatment when expressed on a per-mg-of-microsomal-protein basis, but the rate of Me2SO oxidation expressed on a per-nmol-of-P-450 basis was unchanged. Addition of iron-chelating agents to the three different types of microsomal preparations caused an ‘uncoupling’ of the electron-transport chain accompanied by a 4-fold increase of the rate of Me2SO oxidation. It is concluded that ethanol treatment results in the induction of P-450 forms specifically effective in ethanol oxidation and NADPH oxidation, but not in hydroxyl-radical production, as detected by the oxidation of Me2SO.

scholarly journals Synthesis, Characterization and Solution Chemistry of trans-Indazoliumtetrachlorobis(Indazole)Ruthenate(III), a New Anticancer Ruthenium Complex. IR, UV, NMR, HPLC Investigations and Antitumor Activity. Crystal Structures of trans-1-Methyl-Indazoliumtetrachlorobis-(1-Methylindazole)Ruthenate(III) and its Hydrolysis Product trans-Monoaquatrichlorobis-(1-Methylindazole)-Ruthenate(III)

1996 ◽  
Vol 3 (5) ◽  
pp. 243-260 ◽  
Author(s):  
Kari-Georg Lipponer ◽  
Ellen Vogel ◽  
Bernhard K. Keppler
Keyword(s):  
Antitumor Agents ◽  
Ruthenium Complex ◽  
Hydrolysis Product ◽  
Order Rate Constant ◽  
Solution Chemistry ◽  
Molecular Structures ◽  
Physiological Conditions ◽  
Cell Dimensions ◽  
Competitive Products ◽  
Hydrolysis Of

Besides intensive studies into the synthesis of the complex trans-Hlnd[RuCl4(ind)2] (Ind = indazole) 1, which differs remarkably from the usual method for the complexes of the HL[RuCl4L2] - type, competitive products and hydrolysis of this species are described. Stability and pseudo-first-order rate constant under physiological conditions of complex 1 in comparison with the analogous imidazole complex trans-Hlm[RuCl4(im)2] (Im = imidaZole) ICR were examined by means of HPLC, UV and conductivity measurements (Kobs.(1) = 1.55 × 10-4s-1; Kobs.(ICR) = 9.10 × 10-4s-1). An attempt was made to elucidate the bonding conditions in 1 by studying the reactions of Ru(lll) and the two N-methyl isomers of indazole. It can be expected that bonding in the unsubstituted ligand should occur via the N2 nitrogen. The molecular structures of the complex trans-H(1-Melnd)[RuCl4(1-Melnd)2] × 1H2O (1-Melnd = 1-methylindazole) 6 and its hydrolysis product in aqueous solution [RuCl3(H2O)(1-Melnd)2]7 were determined crystallographically. After anisotropic refinement of F values by least squares, R is 0.053 for 6 and 0.059 for 7. Both complexes crystallize with four molecules in a unit cell of monoclinic symmetry. The space group is P2.1/n for 6 with cell dimensions a = 10.511Å, b = 13.87Å, c = 19.93Å, and β = 98.17° and C2/c for 7 with a = 19.90Å, b = 10.94Å, c = 8.490Å and β = 96.74° The fact that the aqua species 7 could be isolated after dissolving 6 in a water/acetone solution confirmed the theory of many Ru(lll) complexes being initially transformed, under physiological conditions, into aqua complexes in a first and often rate-determining hydrolysis step. Compounds 1 and ICR are potent antitumor agents which exhibit activity against a variety of tumor cells and experimental tumor models in animals, including autochthonous colorectal tumors. Clinical studies with 1 are in preparation.

scholarly journals Insight into the nature and site of oxygen-centered free radical generation by endothelial cell monolayers using a novel spin trapping technique

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 699-707 ◽  
Author(s):  
BE Britigan ◽  
TL Roeder ◽  
DM Shasby
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Free Radical ◽  
Hydroxyl Radical ◽  
Spin Trap ◽  
Spin Trapping ◽  
Cathepsin G ◽  
Cell Monolayers ◽  
Radical Production ◽  
Radical Generation

Abstract Spin trapping, a sensitive and specific means of detecting free radicals, is optimally performed on cell suspensions. This makes it unsuitable for the study of adherent endothelial cell monolayers because disrupting the monolayer to induce a cell suspension could introduce confounding factors. This problem was eliminated through the use of endothelial cells that were grown to confluence on microcarrier beads. Using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), the nature of free radical species generated by suspensions of microcarrier bead adherent porcine pulmonary endothelial cells under various forms of oxidant stress was examined. Exposure of these endothelial cells to paraquat resulted in the spin trapping of superoxide (.O2-). Endothelial cell incubation in the presence of either bolus or continuous fluxes of hydrogen peroxide (H2O2) yielded spin trap evidence of hydroxyl radical formation, which was preventable by pretreating the cells with deferoxamine. Chromium oxalate which eliminates extracellular electron paramagnetic resonance spectrometry (EPR) signals, prevented the detection of DMPO spin adducts generated by paraquat but not H2O2-treated endothelial cells. When endothelial cells were coincubated with PMA-stimulated monocytes evidence of both .O2- and hydroxyl radical production was detected, whereas with PMA- stimulated neutrophils only .O2- production could be confirmed. Neutrophil elastase, cathepsin G, and the combination of PMA and A23187 have previously been suggested to induce endothelial cell oxy-radical generation. However, exposure of endothelial cells to each of these agents did not yield DMPO spin adducts or cyanide-insensitive endothelial cell O2 consumption. These data indicate that endothelial cell exposure: to paraquat induces extracellular .O2- formation; to H2O2 leads to intracellular hydroxyl radical production; and to elastase, cathepsin G, or A23187/PMA does not appear to cause oxy- radical generation.

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