Azathioprine and UVA Light generate mutagenic oxidative DNA damage

O'Donovan, Peter; Perrett, Conal M.; Zhang, Xiaohong; Montaner, Beatriz; Xu, Yao-Zhong; Harwood, Catherine A.; McGregor, Jane M.; Walker, Susan L.; Hanaoka, Fumio and Karran, Peter (2005). Azathioprine and UVA Light generate mutagenic oxidative DNA damage. Science, 309(5742) pp. 1871–1874.

DOI: https://doi.org/10.1126/science.1114233

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.

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