Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light.
DNA Repair (Amst)
; 6(3): 344-54, 2007 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-17188583
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.
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Base de dados:
MEDLINE
Assunto principal:
Tioguanina
/
Raios Ultravioleta
/
Dano ao DNA
/
Antimetabólitos Antineoplásicos
Limite:
Female
/
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article