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British Medical Bulletin Advance Access originally published online on February 2, 2007
British Medical Bulletin 2006 79-80(1):153-170; doi:10.1093/bmb/ldl020
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© The Author 2007. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Thiopurines, DNA damage, DNA repair and therapy-related cancer

Peter Karran*

Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK

* Correspondence to: Peter Karran, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK. E-mail: peter.karran{at}cancer.org.uk

Aims: The thiopurines, azathioprine, 6-mercaptopurine and 6-thioguanine are one of the success stories of chemotherapy. They are effective immunosuppressants and anti-cancer agents and are prescribed increasingly to treat inflammatory diseases. Although their metabolism has been studied in detail, the optimal use of thiopurines has been guided predominantly by clinical experience and the precise molecular events that underlie their therapeutic activity have remained unclear. The aim of this article is to review some of the properties of the thiopurines and relate them to possible therapeutic mechanisms. In particular, I consider the contribution that DNA substitution by 6-thioguanine makes to their effects as well as some of the possible harmful reactions that DNA 6-thioguanine might undergo.

Conclusions: The increased chemical reactivity of DNA 6-thioguanine underlies its cytotoxic effects and is an important contributor to the anti-leukaemic effects of the thiopurines. The same enhanced reactivity may contribute to the increased risk of acute myeloid leukaemia and skin cancer in thiopurine-treated organ transplant patients.

Keywords: Thiopurines • azathioprine • 6-thioguanine • 6-mercaptopurine • DNA mismatch repair • oxidative DNA damage • skin cancer • acute myeloid leukaemia

Accepted for publication December 21, 2006.


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