title: Azathioprine and UVA light generate mutagenic oxidative DNA damage.
abstract: Oxidative stress and mutagenic DNA lesions formed by reactive oxygen species (ROS) are linked to human malignancy. Clinical treatments inducing chronic oxidative stress may therefore carry a risk of therapy-related cancer. We suggest that immunosuppression by azathioprine (Aza) may be one such treatment. Aza causes the accumulation of 6-thioguanine (6-TG) in patients' DNA. Here we demonstrate that biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with 6-TG-substituted DNA and that 6-TG and UVA are synergistically mutagenic. A replication-blocking DNA 6-TG photoproduct, guanine sulfonate, was bypassed by error-prone, Y-family DNA polymerases in vitro. A preliminary analysis revealed that in five of five cases, Aza treatment was associated with a selective UVA photosensitivity. These findings may partly explain the prevalence of skin cancer in long-term survivors of organ transplantation.
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Donovan
authors.forename: Conal M
authors.initials: CM
authors.lastname: Perrett
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Beatriz
authors.initials: B
authors.lastname: Montaner
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Xu
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Harwood
authors.forename: Jane M
authors.initials: JM
authors.lastname: McGregor
authors.forename: Susan L
authors.initials: SL
authors.lastname: Walker
authors.forename: Fumio
authors.initials: F
authors.lastname: Hanaoka
authors.forename: Peter
authors.initials: P
authors.lastname: Karran
mesh_terms: D000228:Adenine Phosphoribosyltransferase / Q000235:genetics; D001379:Azathioprine / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D016296:Mutagenesis; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010787:Photosensitivity Disorders; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D013866:Thioguanine / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D014466:Ultraviolet Rays
chemical_list: D017382:Reactive Oxygen Species; D004247:DNA; D000228:Adenine Phosphoribosyltransferase; D004259:DNA-Directed DNA Polymerase; D013866:Thioguanine; D001379:Azathioprine