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Science 16 September 2005:
Vol. 309. no. 5742, pp. 1871 - 1874
DOI: 10.1126/science.1114233
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Reports

Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage

Peter O'Donovan,1 Conal M. Perrett,1,3 Xiaohong Zhang,1,2 Beatriz Montaner,1 Yao-Zhong Xu,2 Catherine A. Harwood,3 Jane M. McGregor,3 Susan L. Walker,4 Fumio Hanaoka,5 Peter Karran1*

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.

1 Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
2 Department of Chemistry, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK.
3 Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and The London Queen Mary's School of Medicine and Dentistry, 4, Newark Street, London, E1 2AT, UK.
4 Department of Photobiology, Guy's, King's and St Thomas' School of Medicine, St. John's Institute of Dermatology, King's College, London SE1 7EH, UK.
5 RIKEN Discovery Research Institute, Wako-shi, Saitama 351-0198 Japan.

* To whom correspondence should be addressed. E-mail: peter.karran{at}cancer.org.uk

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Science. ISSN 0036-8075 (print), 1095-9203 (online)