title: Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light.
abstract: The therapeutic effect of the thiopurines, 6-thioguanine (6-TG), 6-mercaptopurine, and its prodrug azathioprine, depends on the incorporation of 6-TG into cellular DNA. Unlike normal DNA bases, 6-TG absorbs UVA radiation, and UVA-mediated photochemical damage of DNA 6-TG has potentially harmful side effects. When free 6-TG is UVA irradiated in solution in the presence of molecular oxygen, reactive oxygen species are generated and 6-TG is oxidized to guanine-6-sulfonate (G(SO3)) and guanine-6-thioguanine in reactions involving singlet oxygen. This conversion is prevented by antioxidants, including the dietary vitamin ascorbate. DNA G(SO3) is also the major photoproduct of 6-TG in DNA and it can be selectively introduced into DNA or oligonucleotides in vitro by mild chemical oxidation. Thermal stability measurements indicate that G(SO3) does not form stable base pairs with any of the normal DNA bases in duplex oligonucleotides and is a powerful block for elongation by Klenow DNA polymerase in primer extension experiments. In cultured human cells, DNA damage produced by 6-TG and UVA treatment is associated with replication inhibition and provokes a p53-dependent DNA damage response.
authors.affiliation: Department of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Graham
authors.initials: G
authors.lastname: Jeffs
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Ren
authors.forename: Peter
authors.initials: P
authors.lastname: O'Donovan
authors.forename: Beatriz
authors.initials: B
authors.lastname: Montaner
authors.forename: Conal M
authors.initials: CM
authors.lastname: Perrett
authors.forename: Peter
authors.initials: P
authors.lastname: Karran
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Xu
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000528:radiation effects* / Q000633:toxicity*; D001190:Arylsulfonates / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004261:DNA Replication; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D010083:Oxidants, Photochemical / Q000378:metabolism; D010084:Oxidation-Reduction / Q000528:radiation effects; D013866:Thioguanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000528:radiation effects* / Q000633:toxicity*; D014466:Ultraviolet Rays
chemical_list: D000964:Antimetabolites, Antineoplastic; D001190:Arylsulfonates; D010083:Oxidants, Photochemical; C520547:guanine-6-sulfonate; C520548:guanine-6-thioguanine; D006147:Guanine; D004247:DNA; D013866:Thioguanine