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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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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Mutagenic and Cytotoxic Properties of 6-Thioguanine, S6-Methylthioguanine, and Guanine-S6-sulfonic Acid.
B. Yuan and Y. Wang (2008)
J. Biol. Chem. 283, 23665-23670
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Cancer in patients on dialysis and after renal transplantation.
M. Fischereder (2008)
Nephrol. Dial. Transplant. 23, 2457-2460
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IL-10 Controls Ultraviolet-Induced Carcinogenesis in Mice.
K. Loser, J. Apelt, M. Voskort, M. Mohaupt, S. Balkow, T. Schwarz, S. Grabbe, and S. Beissert (2007)
J. Immunol. 179, 365-371
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In vitro replication and thermodynamic studies of methylation and oxidation modifications of 6-thioguanine.
C. Gu and Y. Wang (2007)
Nucleic Acids Res. 35, 3693-3704
   Abstract »    Full Text »    PDF »
Malignancies in renal transplantation: an unmet medical need.
J. Dantal and E. Pohanka (2007)
Nephrol. Dial. Transplant. 22, i4-i10
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Azathioprine, UV light, and skin cancer in organ transplant patients--do we have an answer?.
C. Ulrich and E. Stockfleth (2007)
Nephrol. Dial. Transplant. 22, 1027-1029
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Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV-specific tandem CC to TT mutations of the p53 gene.
S. Queille, L. Luron, A. Spatz, M. F. Avril, V. Ribrag, P. Duvillard, C. Hiesse, A. Sarasin, J. P. Armand, and L. Daya-Grosjean (2007)
Carcinogenesis 28, 724-731
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Thiopurines, DNA damage, DNA repair and therapy-related cancer.
P. Karran (2007)
Br. Med. Bull.
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Enhanced photocarcinogenesis in interleukin-12-deficient mice..
A. Maeda, S. W. Schneider, M. Kojima, S. Beissert, T. Schwarz, and A. Schwarz (2006)
Cancer Res. 66, 2962-2969
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Immunosuppression, Skin Cancer, and Ultraviolet A Radiation.
J. A. Parrish (2005)
N. Engl. J. Med. 353, 2712-2713
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Radical Ideas About Azathioprine and Cancer.
(2005)
Journal Watch Dermatology 2005, 7
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Science. ISSN 0036-8075 (print), 1095-9203 (online)