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Biomedical subjects

D I Edwards

Publications and source records attributed to D I Edwards.

At least 37 records · Page 2Linked to original sources
PubMed1991

A comparison of the relative activities of 8 radiosensitizers in the SOS chromotest.

Misonidazole, and RSU 1069 and 6 of its analogues are all reported to show increased cytotoxicity towards hypoxic cells compared to oxic cells. DNA is considered to be the target through which these drugs exert their cytotoxic activity. Therefore we monitored induction of the SOS response in uvrABC excinuclease proficient and deficient strains of E. coli, under oxic and hypoxic conditions, as an indirect method of assessing the activity of these drugs towards DNA in a biological system. This was done using the SOS chromotest which utilizes E. coli strains which possess a sfiA::lacZ fusion allowing induction of the SOS response to be monitored by assaying beta-galactosidase activity. All of the drugs tested here show some induction of the SOS response in both uvrABC excinuclease proficient and deficient strains. Data shown here suggests that the uvrABC excinuclease is important in the production of a SOS induction signal from RSU 1069-induced DNA lesions and that RSU 1069 may act as a crosslinking agent. The data also shows that SOS induction activity and toxicity do not necessarily correlate and that production of a SOS induction signal may occur via a different pathway for RSU 1069 than for its analogues.

Cell Hypoxia↗
PubMed1991

Electrochemical studies of nitroheterocyclic compounds of biological interest. VII. Effect of electrode material.

The electrochemical behaviour of three nitrofuran compounds, nitrofurazone, nitrofurantoin and furazolidone, has been studied in three solvent types; aprotic, aqueous and mixed, and at four working electrodes. Particular attention has focused on the 1-electron RNO2/RNO2.- couple as measured by the cyclic voltammetric mode. Using Hg in aqueous buffer, reduction of the NO2 group proceeds directly to the hydroxylamine with no intermediate stages being identified. Addition of an aprotic solvent gave a 2-stage reduction, initially forming the RNO2.- species. At all solid electrodes, however, the RNO2/RNO2.- couple was identified under simple aqueous conditions. The switch to a mixed aqueous/aprotic solvent medium produced only minor changes in the response compared with the situation on Hg. This presents the opportunity of using nitrofuran complexes as model systems for the redox behaviour of nitro aromatic compounds in general at solid electrode surfaces where the latters' more negative reduction potentials makes direct study difficult. The conditions have been defined whereby we can examine pH effects and RNO2.- biological target interactions in simple aqueous media to allow the further refinement of the electrolytic model system for studying bio-reducible drug action.

Carbon↗
PubMed1990

DNA damaging effects and voltammetric studies on the hypoxic cell toxin 3-amino-1,2,4-benzotriazine-1,4-dioxide, SR4233, as a function of pH.

The compound 3-amino-1,2,4-benzotriazine-1,4-dioxide, SR4233, has recently attracted considerable attention as a possible hypoxic cell radiation sensitizer and cytotoxic agent. The present study examines the influence of pH on the DNA damaging ability of SR4233 upon electrolytic reductive activation, and the corresponding changes in electrochemistry. A phi X174 double transfection assay has been employed to assess the DNA damaging ability of SR4233 between pH 4 to 7. Upon electrolytic reduction the drug was found to be more effective in damaging DNA at acidic pH than at neutral conditions. This indicated that the damaging species was probably protonated. The DNA damaging ability of SR4233, as measured by a viral transfection assay, was linearly related to pH between the values of 4 and 7, and this feature has implications for its potential efficacy in the treatment of hypoxic tumors. The electrochemistry of SR4233 has been examined as a function of pH between the ranges 2 and 10.5. Three investigation techniques have been employed, cyclic voltammetry and differential pulse and dc polarographies. A general shift towards less negative potentials with increasing acidity was found between pH 2 and 8.5 giving a linear relationship. The behaviour was found to be relatively invariant at alkaline pH.

Antineoplastic Agents↗
PubMed1990

Electrochemical studies and DNA damaging effects of the benzotriazine-N-oxides.

The electrochemical behaviour of eight benzotriazine 1,4 di-N-oxides has been examined and compared with the mono- and zero-N-oxides. The di-N-oxides all show two reduction steps, an irreversible followed by a quasi-reversible response assigned to the 4 electron reduction of both N-oxide groups, followed by the 2 electron reduction of the benzotriazine ring. Mono- and zero-N-oxides show only a single, quasi-reversible reduction step, similar in character to the second reduction of the di-N-oxides. This has been assigned to reduction of the benzotriazine ring, with the available, redox-active, N-oxide group of the mono-N-oxide complex being reduced at less negative potentials, but only after ring reduction, hence only a single electrode response. The importance of reductive activation of the N-oxide group has been examined using a phi X174 double transfection technique which assays biologically relevant DNA damage. For the di-N-oxides, no effect on DNA was recorded under oxic conditions, however, DNA damage was marked under anoxic reduction conditions. The extent of DNA damage was found to increase with the acidity of the medium, suggesting the protonated form of the reduction product as being responsible for the cytotoxic action. The mono-N-oxide was shown to be biologically inactive under all conditions.

Antineoplastic Agents↗
PubMed1990

Electrochemical characteristics of nitroheterocyclic compounds of biological interest. V. Measurement and comparison of nitro radical lifetimes.

Using mixed aqueous/dimethylformamide solvents we have generated nitro radical anions by electrochemical reduction of nitroaromatic compounds. Six drugs have been examined: metronidazole, nitrofurazone, nifuroxime, chloramphenicol, M&B 4998 and 4(5)-nitroimidazole, chosen to represent a variety of ring structures and a range of reduction potentials. Analysis of the cyclic voltammetric response as a function of scan rate and dimethylformamide content yields information on the reactivity of RNO2.-. A kinetic analysis of the return-to-forward peak current ratio based on a theoretical treatment was employed. Second-order kinetics for the decay of RNO2.- for all six drugs examined was established. By extrapolation, first half-lives in purely aqueous media were found to increase in the order: nitrofurazone, nifuroxime, chloramphenicol, metronidazole and M&B 4998 (from 8.9 x 10(-2) seconds for nitrofurazone to 98s for M&B 4998 at a radical anion concentration of 1 x 10(-6) mol/dm3). Comparison with reduction potentials showed that as the lifetime of RNO2.- increased, the drug became progressively less electron-affinic (reduced at more negative potentials). The reactivity of RNO2.- was also examined in relation to the DNA damaging capability following electrochemical reduction of these nitroaromatic drugs.

Chloramphenicol↗
PubMed1990

Electrochemical characteristics of five quinolone drugs and their effect on DNA damage and repair in Escherichia coli.

The object of this study was to determine whether 4-quinolone antimicrobials were reduced under biologically attainable redox conditions and whether they had any effect on DNA in the absence of the DNA gyrase enzyme. Electrochemical characteristics of the drugs were investigated using d c polarography, differential pulse polarography and cyclic voltammetry. The ability of the drugs to interact with, and cause damage to, naked DNA was investigated by a phi X174 DNA double transfection assay. Induction of DNA SOS repair was assessed using a stain of Escherichia coli in which the synthesis of beta-galactosidase was under the control of the su1A gene. Growth studies were performed using a conductimetric method in a Malthus system. All five 4-quinolones examined had redox potentials lower (more negative) than -1.2 V and thus were incapable of being reduced in biological systems, even under strict anaerobiosis. Exposure of all drugs to single-stranded phi X174 DNA for up to 50 h engendered no detectable damage. However, all the drugs induced DNA SOS repair, in the order ciprofloxacin greater than fleroxacin = pefloxacin greater than norfloxacin greater than nalidixic acid. This rank order corresponds approximately with antibacterial efficiency. The growth studies indicated that redoxyendonuclease III and excision repair enzymes may be involved in the fixation of quinolone-induced damage.

4-Quinolones↗
PubMed1990

Electrochemical characteristics of nitroheterocyclic compounds of biological interest. VI. The misonidazole radical anion.

The addition of four aprotic solvents to misonidazole in an aqueous buffer system has been examined electrochemically. Qualitatively they all result in separation of the initial irreversible 4 electron reduction step into two stages, the RNO2/RNO2- and RNO2-/RNHOH couples respectively. Despite some difficulties in achieving measurements for the discrete RNO2/RNO2- without interference from the following reduction step, it was clear that the various aprotic solvents influenced the lifetime of the RNO2- species to different degrees. Resolution of the two processes was best achieved using a water-acetone system and this has been employed to study the lifetimes of the misonidazole radical anion as a function of acetone content and drug concentration. Analysis of the cyclic voltammetric response showed a second order decay pathway, in line with the metronidazole system studied under similar conditions. This has been compared with results from pulse radiolysis work, which suggested a first order reaction of unknown pathway for 2-nitroimidazole radical anions.

Anions↗
PubMed1990

Electrochemical properties as a function of pH for the benzotriazine di-N-oxides.

The electrochemistry of five benzotriazine di-N-oxides has been examined by cyclic voltammetry and differential pulse and dc polarographies as a function of pH. Between the pH range 8.5 and 2 the trend to less negative potentials with lowering of pH can be described by an equation of the type Ep = -apH + b. Comparison has been made with the mono- and zero-N-oxides which were found to show virtually identical trends in electron affinity with pH. The general electrochemical characteristics for the di- and mono-N-oxides under acidic conditions were found to be comparable with the zero-N-oxide. This was particularly the case on repeat scanning in the cyclic voltammetric mode. The redox mechanism involved reduction by a 4-electron addition step and subsequent loss of the N-oxide group(s) yielding the intact benzotriazine heterocycle. The heterocycle was also redox active, involving a reversible 2-electron reduction. For the di-N-oxides these two stages could be identified as separate processes at alkaline pH, but only a single step at acidic values. The mono-N-oxide in which the electrochemical behaviour was dominated by the triazine, showed only a single reduction step, although the single N-oxide group was redox active.

Antineoplastic Agents↗
PubMed1989

Comparative DNA damage and repair induced by misonidazole, CB 1954 and RSU 1069.

We have studied the ability of CB 1954, misonidazole, and RSU 1069 to induce biologically relevant DNA damage in single- and double-stranded phi X174 DNA under oxic, anoxic, and anoxic reductive conditions using a double transfection technique. In addition, the ability of the three drugs to induce the SOS repair response in E. coli under the same conditions was measured. Whereas the relative order of DNA damage was RSU 1069 greater than CB 1954 greater than misonidazole the order in inducing SOS repair was RSU 1069 greater than misonidazole greater than CB 1954. Drug-induced damage by RSU 1069 involves enhanced damage by endonuclease III suggesting drug-induced pyrimidine damage. There appears to be no correlation between drug-induced damage and the degree of SOS repair induction. Thus it appears that enzymes other than, or in addition to, those of the SOS repair system are involved in the repair of DNA damage induced by these drugs.

Antineoplastic Agents↗
PubMed1989

Electrochemical characteristics of nitro-heterocyclic compounds of biological interest. II. Nitrosochloramphenicol.

The electrochemical characteristics of nitrosochloramphenicol have been studied in aqueous buffer systems (pH 7.1) using direct current (d.c.) and differential pulse polarography, cyclic voltammetry and coulometric techniques. Up to 4 charge-transfer steps can be identified. The first reduction step is reversible both chemically and electrochemically, the charge-transfer product showing no tendency to undergo further reaction on the electrochemical time-scale. In contrast, the second reduction step is irreversible, with the product undergoing a fast following reaction to yield a redox-active species which was detected by cyclic voltammetry. From the data and by comparison with related systems, two reduction mechanisms are possible and are discussed.

Chloramphenicol↗
PubMed1989

Electrochemical characteristics of nitro-heterocyclic compounds of biological interest. III. Nitroso derivative formation.

Upon electrolytic reduction of a range of nitro-aromatic complexes (including imidazoles, benzenoids, furans and pyrazoles) an associated oxidation-reduction process is observed at more positive potentials with respect to nitro group reduction when using repeat scan cyclic voltammetry. This new couple has been identified as the reversible first reduction of the nitroso derivative for chloramphenicol, by the addition of a genuine sample of nitrosochloramphenicol to the electrochemical cell. We have failed to observe formation of the new redox-active species for five 5-nitroimidazoles examined. Possible reaction schemes for nitroso formation under electrolytic reduction conditions and the importance of the nitroso redox couple with respect to the cytotoxic action of the parent drug are discussed. The applicability of nitrosochloramphenicol as a model for the behaviour of nitro-heterocycles in general is shown.

Chloramphenicol↗
PubMed1989

Electrochemical characteristics of nitro-heterocyclic compounds of biological interest. IV. Lifetime of the metronidazole radical anion.

Electrochemical studies on metronidazole using mixed aqueous/dimethylformamide (DMF) solvents have allowed us to generate the one-electron addition product, the nitro radical anion, RNO2(-.). Cyclic volt-ammetric techniques have been employed to study the tendency of RNO2-.to undergo further chemical reaction. The return-to-forward peak current ratio, ipr/ipf, was found to increase towards unity with increasing DMF content of the medium, indicating the extended lifetime of RNO2(-.). Second order kinetics for the decay of RNO2-were established at all DMF concentrations examined. Extrapolation has allowed the rate constant and a first half-life of 8.4 x 10(4) dm3/mol-sec and 0.059 seconds respectively, to be determined for the decay of RNO2-in a purely aqueous media. This is impossible by direct electrochemical measurement in water, due to a different reduction mechanism, giving the hydroxylamine derivative in a single 4-electron step. The application of the technique to other nitro-aromatic compounds is discussed.

Drug Stability↗
PubMed1989

Studies on DNA damage and induction of SOS repair by novel multifunctional bioreducible compounds. I. A metronidazole adduct of dirhodium (II) tetraacetate.

A novel bifunctional hypoxia-selective compound [Rh2(O2CCH3)4.2C6N3O3H9] has been synthesized and its genotoxic and potential mutagenic effects studied with reference to those of dirhodium tetraacetate (RAc) and metronidazole. The properties of the two functional components have been examined by comparing its oxic genotoxicity, a measure of the DNA damage induced by RAc, with its anoxic genotoxicity by electrochemical reduction, a measure of DNA damage resulting from the combined activity of reduced nitro group intermediates and RAc. The induction of DNA SOS repair has also been studied as well as the strand-breaking ability of the compound using viscometry. The genotoxic effects observed are proportional to the drug concentration over the range tested and the compound exhibits a high selective toxicity differential to hypoxic bacteria. The strand-breaking and mutagenic properties are governed by the metronidazole component and other effects, such as inhibition of DNA synthesis, are governed by the RAc component.

DNA↗
PubMed1988

Electrochemical characteristics of nitro-heterocyclic compounds of biological interest. I. The influence of solvent.

The electrochemical properties of three nitroimidazoles, a nitropyrazole, a nitrofuran and three nitrobenzenoid compounds have been extensively investigated in a range of solvents. The reduction pathway for the nitro group is independent of the cyclic function to which it is attached, but is strongly influenced by the nature of the solvent. In aqueous media, generally, a single, irreversible 4-electron reduction occurs to give the hydroxylamine. In aprotic media (dimethylformamide, methylene chloride or dimethylsulphoxide), a reversible one-electron reduction takes place to form a stable nitro radical anion. At more negative values, a further 3-electron reduction occurs, irreversibly to give the hydroxylamine. In mixed aqueous-organic systems, intermediate behaviour is found, with the reversibility of the RNO2/RNO.-2 couple increasing with addition of organic medium. The control of the reduction pathway, by changing the electrolytic medium is discussed in relation to the biological activities of the drugs and identification of the short-lived reduction intermediate responsible for DNA damage.

Electrochemistry↗
PubMed1988

Comparative DNA damage induced by nitroimidazole-aziridine drugs: 1. Effects of methyl substitution on drug action.

RSU-1069 (1-(-3-aziridinyl-2-hydroxypropyl)-2-nitroimidazole) is a bifunctional chemo- and radiosensitizing agent. The properties of these functional groups may be examined by comparison of drug-induced DNA damage oxically, a measure of aziridine-induced damage and, during anoxic electrochemical reduction of the nitro-group, a measure of DNA damage resulting from the combined activity of reduced nitro group intermediates and alkylation by the aziridine moiety. In this study, a series of nitroimidazole aziridines have been studied and compared. The compounds used were RSU-1069, five methyl substituted derivatives: RSU-1131, RSU-1150, RSU-1164, RSU-1172, RB-7040; a 4-nitroimidazole derivative, RSU-1170, and RSU-1137, the non-alkylating hydrolysis product of RSU-1069. DNA damage, occurring oxically or as a consequence of nitro reduction, decreases with increasing substitution of the aziridine ring. Most DNA damage occurring oxically is produced by RSU-1069 and RSU-1170, both compounds having unsubstituted aziridine rings; least DNA damage is produced by RSU-1137. In general, the extent of DNA damage during electrochemical reduction is greater than that occurring oxically, this being due to an assumed combination of alkylation and reduced nitro-group intermediates. There is a direct correlation between the half-lives of the compounds and the extent of DNA damage occurring under oxic conditions. A direct correlation of the aerobic toxicities of the compounds tested, relative to RSU-1069, and the number of unsubstituted sites available for nucleophilic attack on the aziridine moiety has also been shown.

Coliphages↗
PubMed1987

DNA damage induced by reduced nitroimidazole drugs.

Five nitroimidazole drugs were reduced electrolytically and by gamma-radiolysis at fast (300 mumoles or 100% per hr) and slow (3-9 mumoles or 1-3% per hr) reduction rates in the presence of Escherichia coli DNA and single stranded or double stranded DNA from the bacteriophage phi X174. The degree of DNA damage depends upon the rate of drug reduction, where slow reduction produces more damage than fast reduction. The efficiency of damage produced is in the order metronidazole greater than ornidazole greater than azomycin greater than misonidazole greater than benznidazole which reveals a linear correlation between the one-electron reduction potential (E17) and the negative logarithm of the concentration of reduced drug at which 37% of the original DNA activity remains. Damage is not influenced by the presence of O2 at least between about 1-100 ppm. We suggest the protonated one-electron nitro radical anion as a possible candidate for the active damaging species and explain the basis of the relative cytotoxicity of these drugs under conditions of hypoxia.

DNA↗