PubMed Health⌕ Search

Biomedical subjects

N S Virk

Publications and source records attributed to N S Virk.

5 recordsLinked to original sources
PubMed1992

Repair of damage induced by SR 4233.

The benzotriazine di-N-oxide, SR 4233, was electrolytically reduced at constant potential at pH 4.0 at a reduction rate of 5%/hr under N2 in the presence of phi X174 DNA. During the reduction process, the biological infectivity of the bacterial phage was measured by a double transfection technique, either into the wild-type Escherichia coli strain, or into a series of seven mutants with specific, known defects in their capacity to repair DNA. The survival of phi X174 was evaluated as an index of drug damage and from this we conclude that SR 4233 induces pH-dependent DNA damage in E coli, which is recognized and repaired primarily by the uvrC gene product and by the exonuclease III and endonuclease III gene products. These gene products act primarily upon and are responsible for the recognition of strand breaks and repair of oxidized and fragmented pyrimidine products, indicating that SR 4233 induces strand breaks in DNA resulting from oxidative damage to pyrimidines. As damage is maximized at acid pH, we further propose that the damage mechanism is a process of electron transfer from pyrimidine nucleotides in DNA (i.e., oxidation) to the protonated benzotriazine di-N-oxide one-electron radical anion.

Antineoplastic Agents↗
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 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↗