Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light

• Published in: DNA repair 2007-03, Vol.6 (3), p.344-354
• Main Authors: Zhang, Xiaohong, Jeffs, Graham, Ren, Xiaolin, O’Donovan, Peter, Montaner, Beatriz, Perrett, Conal M., Karran, Peter, Xu, Yao-Zhong
• Format: Article
• Language: English
• Subjects: 6-Thioguanine; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - radiation effects; Antimetabolites, Antineoplastic - toxicity; Antioxidants; Arylsulfonates - chemistry; Arylsulfonates - metabolism; Bacteriology; Biological and medical sciences; Cell Line, Tumor; DNA - chemistry; DNA - metabolism; DNA - radiation effects; DNA Damage; DNA photoproducts; DNA Replication; Dose-Response Relationship, Radiation; Female; Fundamental and applied biological sciences. Psychology; Growth, nutrition, cell differenciation; Guanine - analogs & derivatives; Guanine - chemistry; Guanine - metabolism; Guanine-6-sulfonate; Humans; Microbiology; Molecular and cellular biology; Molecular genetics; Mutagenesis. Repair; Oxidants, Photochemical - metabolism; Oxidation-Reduction - radiation effects; Oxidative DNA damage; Photochemistry; Reactive oxygen species; Rose Bengal; Thioguanine - analogs & derivatives; Thioguanine - chemistry; Thioguanine - metabolism; Thioguanine - radiation effects; Thioguanine - toxicity; Ultraviolet light; Ultraviolet Rays; UVA
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2006.11.003

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.