DNA strand breakage

Depurination - N7 alkylation may cause cleavage of the imidazole ring and excision of the guanine residue, leading to DNA strand breakage. 

Chromosome function Quinolones Metronidazole (also ) Nitrofu rantoin Rifampicin (also ) 5-Fluorocytosine Inhibit DNA gyrase DNA strand breakage DNA strand breakage Inhibits RNA polymerase Inhibits DNA synthesis No action on mammalian equivalent Requires anaerobic conditions not present in mammalian cells No action on mammalian equivalent Converted to active form in fungi... 

Topoisomerase An enzyme that uncoils DNA during replication by cutting the DNA. Topoisomerase inhibitors prevent DNA from sealing the cut, which causes DNA strand breakage. 

Bleomycin -antitumor antibiotic that causes DNA strand breakage -dose-related pneumonitis -mucocutaneous effects (stomatitis, mucositis) -acute pulmonary edema -fever in 50% -hyperpigmentation (can rarely be DLT)... 

Carboplatin -atypical alkylating agent leading to DNA strand breakage during replication -bone marrow suppression—particularly thrombocytopenia -nausea and vomiting -liver function test abnormalities -uncommon neurotoxicity, ototoxicity... 

Xanthine oxidase, a widely used source of superoxide, has been frequently applied for the study of the effects of superoxide on DNA oxidation. Rozenberg-Arska et al. [30] have shown that xanthine oxidase plus excess iron induced chromosomal and plasmid DNA injury, which was supposedly mediated by hydroxyl radicals. Ito et al. [31] compared the inactivation of Bacillus subtilis transforming DNA by potassium superoxide and the xanthine xanthine oxidase system. It was found that xanthine oxidase but not K02 was a source of free radical mediated DNA inactivation apparently due to the conversion of superoxide to hydroxyl radicals in the presence of iron ions. Deno and Fridovich [32] also supposed that the single strand scission formation after exposure of DNA plasmid to xanthine oxidase was mediated by hydroxyl radical formation. Oxygen radicals produced by xanthine oxidase induced DNA strand breakage in promotable and nonpromotable JB6 mouse epidermal cells [33]. 

It is known that peroxynitrite is able to induce DNA strand breakage, which activates nuclear enzyme poly(ADP ribose) synthase (PARS). Szabo et al. [257] showed that the inhibition of PARS by oral treatment with lipophilic inhibitor 5-iodo-6-amino-l,2-benzopyr-one delayed the onset of arthritis in rats. It is possible that infrared pulse laser therapy can be useful for the treatment of RA patients [258]. 

This enables one to use aliphatic systems as precursors to the radicals X-Y whose solvolytic (= redox) behavior can then be studied. Equations 2a, c describe what may be called oxidative solvolysis . This reaction sequence, the first step of which is in many cases induced by the OH radical, is of great importance in radical (and radiation) chemistry. It extends from /8-elimination reactions of monomeric radicals [6, 7] to the mechanism of DNA strand breakage [8]. An example for Eq. 2 in which it is shown that the radical XY can be produced by either step a or b is given in section 3.3. 

Figure 21.11 Role of p53 as a tumour suppressor gene. p53 induces a cell with damaged DNA either to initiate apoptosis, or arrest the cell cycle, to give time for damaged DNA to be repaired. Damage can be, for example, a mutation, DNA strand breakage or chromosomal rearrangement.

Kluza J, Mazinghien R, Irwin H, Hartley JA, Bailly C. (2006) Relationships between DNA strand breakage and apoptotic progression upon treatment of HL-60 leukemia cells with tafluposide or etoposide. Anti-Cancer Drugs 17 155-164. 

In genotoxic assays in vivo treatment induced sister chromatid exchanges in the bone marrow of mice, and DNA strand breakage was induced in the liver and kidney of rats. / vitro aniline was not mutagenic to bacteria and did not cause DNA damage. ... 

NMOR is mutagenic in bacterial assays in the presence of activated liver microsomal fractions. However, NMOR did not induce DNA damage in either human or rat kidney cells in vitro as determined by DNA strand breakage. ... 

Robinson SH, Costa M. 1982. The induction of DNA strand breakage by nickel compounds in cultured Chinese hamster ovary cells. Cancer Ixtt 15 35-40. 

A number of 1-substituted 2(l//)-pyrazinone derivatives show antithrombotic activity as selective inhibitors of the tissue Factor Vila complex <2003BML23I9> and were examined as mast cell tryptase inhibitors <2004BML48I9>. As a curious effect, dihydropyrazines proved to show DNA strand-breakage activity <2005CPB1359>. 

An alternative method to investigate DNA strand breakage by OH radicals considers the surface accessibility of hydrogen atoms of the DNA backbone [102]. The solvent accessibility is 80% for the sugar-phosphates and —20% for the bases. This method allows a more direct determination of reaction of OH radicals with the individual deoxyribose hydrogens [103,104]. Recent studies show trends in reactivity of OH radicals closely follow the accessibility of the solvent to various deoxyribose hydrogens [105,106]. 

In vivo, neither covalent binding to DNA nor DNA strand breakage was induced in several studies on rat liver, and unscheduled DNA s mthesis was not induced in the liver of either rats or mice. Gene mutations were not induced in the liver of dosed mice in a single study and there was no evidence for induction of chromosomal aberrations in mice or rats. Aberrations were induced, however, in the embryos of dosed pregnant Syrian hamsters. Dominant lethal effects were reported to be induced in male mice, but re-evaluation of these data did not confirm this conclusion. 

In cultured mammalian cells, acrylonitrile induced DNA strand breakage, gene mutation, sister chromatid exchanges and chromosomal aberrations, but not aneuploidy or unscheduled DNA synthesis in rat hepatocytes, at least if the silver grain counting method was used. [Studies using the less reliable scintillation counting method have not been summarized.] Cell transformation was induced in several test systems and gap-junctional intercellular communication was inhibited in one study with Chinese hamster V79 cells. 

In studies with human cells in vitro, acrylonitrile induced DNA strand breakage in a single study, gene mutations in two studies and sister chromatid exchanges in two of three studies, but not unscheduled DNA synthesis or chromosomal aberrations in single studies. 

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