DNA damages

The hydroxylation of single- and double-stranded DNA are changes characteristic of free-radical attack (reviewed by Winyard et al., 1992). An important mechanism is site-specific OH generation, catalysed by iron bound to 

Altered chemical, physicochemical, and structural properties of damaged DNA are reflected in its redox behavior, which is utilized in numerous techniques of DNA damage detection. Electrochemical DNA-based biosensors have been used not only to detect but also to induce and control DNA damage at the electrode surface via electrochemical generation of the damaging (usually radical) species [13]. This way, chemicals and drugs such as niclosamide, adriamycin. 

Experimental arrangement for electrochemical DNA h34 ridiza-tion biosensors includes the following  

These types of DNA detection can also be applied to studies of antioxidative properties of various natural substances preserving DNA from damage [49, 50]. The detection scheme exploits quantification of the DNA portion that survives previous incubation of the biosensor in a mixture of the DNA cleavage agent and antioxidant/mixture of antioxidants under investigation. Using this approach, yeast polysaccharides, phenolic acids such as rosmarinic and caffeic acids, selected flavonoids, as well as aqueous plant extracts and tea extracts were studied [51]. 

In contrast to analysis with HMDE, MFE, or AgSAE, measurements of the guanine oxidation signal at carbon electrodes (GCE, CPE, SPCE) cannot provide information about formation of individual sb due to a lack of differences in the signal intensity of sc and dsDNA (both oc and lin DNA that possess free ends) but can be used for monitoring deep DNA degradation, involving 

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Sulfur dioxide shows some mutagenic effects in microorganisms and fruit flies. Human lymphocyte DNA damage has been observed. It is an equivocal tumorigenic agent by RTECS criteria (183). 

Mouse visible or eleetrophoretie specifie-locus tests Assays for skeletal and cataract mutations Cytogenetic analy.sis and heritable translocation assays DNA damage and repair in rodent germ cells Dominant lethal assay... 

In addition to direct effects of chemical compounds on the fetus, metabolic disturbances in the mother, such as diabetes or hyperthermia, or deficiencies of calories or specific nutrients such as vitamin A, zinc, and folic acid may lead to teratogenesis. Compounds that inhibit placental functions may also induce malformations, e.g., by inhibiting placental circulation. For example, hydroxyurea disrupts the placental circulation and induces malformations. In addition, it also induces DNA damage. 

Camptothecin is a plant alkaloid that selectively targets topoisomerase I (Topi). It produces DNA damage leading to the destruction of eukaryotic cells. Because... 

Camptothecins. Figure 3 Conversion of reversible Topi -DNA cleavage complexes into DNA damage by collision of a replication fork (the DNA polymerase complex is not shown). 

Though DNA damage-based therapies havebeen in use for many years, it has remained unclear why such treatment often causes the selective death of tumor cells while sparing adjacent normal tissue. The genetic alterations that occur in cancers that alter the DNA damage reponse may explain why such therapy can be efficacious. 

Cell Cycle Control. Figure 3 The DNA damage checkpoint. In response to DNA damage cells activate p53 dependent and independent checkpoint pathways leading to cell cycle arrest at G1/S and G2/M allowing DNA repair. If the cellular damage cannot be repaired, cells can initiate apoptosis. 

In contrast, UCN-01, a staurosporine derivative, acts as a potent inhibitor of the Chkl kinase and efficiently abrogates the G2 checkpoint upon DNA damage. Die forced entry into mitosis in the presence of DNA damage results in a mitotic form of apoptosis. Several clinical trials are currently exploring a combined treatment with UCN-01 and various DNA damaging diugs. In the same vein, inhibitors of Chk2 are developed and tested in clinical trials. 

In contrast to the DNA damage checkpoint, the mitotic spindle checkpoint is essential for cell viability. Dierefore, targeting kinases of the spindle checkpoint including Bubl, BubRl, and Mpsl might be a valid strategy for anticancer treatment. 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

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