Cytotoxicity, DNA cross-linking, and DNA single-strand breaks induced by cyclophosphamide in a rat leukemia in vivo

1993 ◽  
Vol 31 (5) ◽  
pp. 381-386 ◽  
Author(s):  
Ji-Yi Wang ◽  
Greg Prorok ◽  
William P. Vaughan
Genetics ◽  
1974 ◽  
Vol 78 (1) ◽  
pp. 139-148
Author(s):  
R B Painter

ABSTRACT Damage in DNA after irradiation can be classified into five kinds: base damage, single-strand breaks, double-strand breaks, DNA-DNA cross-linking, and DNA-protein cross-linking. Of these, repair of base damage is the best understood. In eukaryotes, at least three repair systems are known that can deal with base damage: photoreactivation, excision repair, and post-replication repair. Photoreactivation is specific for UV-induced damage and occurs widely throughout the biosphere, although it seems to be absent from placental mammals. Excision repair is present in prokaryotes and in animals but does not seem to be present in plants. Post-replication repair is poorly understood. Recent reports indicate that growing points in mammalian DNA simply skip past UV-induced lesions, leaving gaps in newly made DNA that are subsequently filled in by de novo synthesis. Evidence that this concept is oversimplified or incorrect is presented.—Single-strand breaks are induced by ionizing radiation but most cells can rapidly repair most or all of them, even after supralethal doses. The chemistry of the fragments formed when breaks are induced by ionizing radiation is complex and poorly understood. Therefore, the intermediate steps in the repair of single-strand breaks are unknown. Double-strand breaks and the two kinds of cross-linking have been studied very little and almost nothing is known about their mechanisms for repair.—The role of mammalian DNA repair in mutations is not known. Although there is evidence that defective repair can lead to cancer and/or premature aging in humans, the relationship between the molecular defects and the diseased state remains obscure.


1973 ◽  
Vol 55 (2) ◽  
pp. 324 ◽  
Author(s):  
Ahmed El-Metainy ◽  
Shigemitsu Tano ◽  
Keiji Yano ◽  
Hikoyuki Yamaguchi

2019 ◽  
Vol 48 (3) ◽  
pp. e13-e13 ◽  
Author(s):  
Le P Ngo ◽  
Norah A Owiti ◽  
Carol Swartz ◽  
John Winters ◽  
Yang Su ◽  
...  

Abstract Genotoxicity testing is critical for predicting adverse effects of pharmaceutical, industrial, and environmental chemicals. The alkaline comet assay is an established method for detecting DNA strand breaks, however, the assay does not detect potentially carcinogenic bulky adducts that can arise when metabolic enzymes convert pro-carcinogens into a highly DNA reactive products. To overcome this, we use DNA synthesis inhibitors (hydroxyurea and 1-β-d-arabinofuranosyl cytosine) to trap single strand breaks that are formed during nucleotide excision repair, which primarily removes bulky lesions. In this way, comet-undetectable bulky lesions are converted into comet-detectable single strand breaks. Moreover, we use HepaRG™ cells to recapitulate in vivo metabolic capacity, and leverage the CometChip platform (a higher throughput more sensitive comet assay) to create the ‘HepaCometChip’, enabling the detection of bulky genotoxic lesions that are missed by current genotoxicity screens. The HepaCometChip thus provides a broadly effective approach for detection of bulky DNA adducts.


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