Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer

Key Points

  • The thiopurines azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) have been available to medical practitioners for over half a century. They are used as anticancer and immunosuppressive agents. The introduction of azathioprine as an immunosuppressant revolutionized solid-organ transplantation from unrelated donors and resulted in much improved graft survival. The thiopurines are recognized treatment options for an increasing number of chronic inflammatory and autoimmune disorders, including arthritis and colitis.

  • Largely on the basis of epidemiological data of cancer in transplant patients, the International Agency for Research on Cancer classifies azathioprine as a human carcinogen. Much of this increased cancer can be attributed to the effects of immunosuppression and the involvement of oncogenic viruses. In some cases, however, demonstration of a viral aetiology has proved elusive. This is particularly true of skin cancer, which is the major treatment-related cancer among transplant patients.

  • Thiopurines are prodrugs and one outcome of their complex metabolism is the incorporation of 6-TG into DNA during replication. 6-TG is chemically more reactive than canonical DNA bases and undergoes methylation in situ in DNA. Methylated DNA 6-TG is ultimately cytotoxic by a mechanism that depends on the cell's DNA mismatch repair system.

  • One route of escape from the cytotoxicity of thiopurines is by inactivation of mismatch repair. Mismatch repair defects are associated with high rates of spontaneous mutation and are common in certain types of cancer. Acute myeloid leukaemia occurs more frequently than expected in transplant patients. These azathioprine-related cancers are often defective in mismatch repair.

  • DNA 6-TG is also photochemically reactive and has a maximum absorbance at 340 nm in the UVA region of the ultraviolet spectrum. UVA comprises more than 90% of solar radiation that reaches the earth and, on exposure to UVA, the 6-TG DNA chromophore generates reactive oxygen species (ROS), which can damage DNA, proteins and other cellular macromolecules.

  • DNA 6-TG itself is particularly susceptible to oxidation by ROS to form guanine-6-sulphonate. This photoproduct is a powerful block to replication but can be bypassed by Y-family polymerases which have a relatively relaxed stringency. The photochemical reactions of DNA 6-TG are mutagenic and this might contribute to an increased risk of transplant-related squamous cell carcinoma of the skin.

  • The association of azathioprine with therapy-related cancers and its increasing use in treatment of chronic inflammatory and autoimmune disorders suggests that careful monitoring of these patients for signs of possible therapy-related cancer is advisable.

Abstract

Thiopurines have diverse clinical applications and their long-term use as anti-rejection drugs in transplant patients has been associated with a significantly increased risk of various types of cancer. Although they are slowly being replaced by a new generation of non-thiopurine immunosuppressants, it is anticipated that their use in the management of inflammatory and autoimmune diseases will continue to increase. Therapy-related cancer will remain a potential consequence of prolonged treatment for these generally non-life-threatening conditions. Understanding how thiopurines contribute to the development of cancer will facilitate clinical decisions about the potential risks to patients of long-term treatment for chronic inflammatory disorders.

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Figure 1: Immunosuppressant therapy in transplant patients.
Figure 2: Thiopurines and their metabolism.
Figure 3: DNA mismatch repair and its contribution to potentially lethal DNA damage.
Figure 4: Absorbance spectra of 6-TG and G.
Figure 5: Reactive oxygen species (ROS) and potential damage to cellular macromolecules.

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Acknowledgements

We are indebted to the numerous laboratory colleagues, past and present, who helped shape many of these opinions, especially to J. Offman, P. O'Donovan and C. Perrett, who contributed particularly to our studies of therapy-related cancer. Many of the ideas expressed in this article have been developed and refined over several years. We thank M. Bignami, Y.-Z. Xu, P. Swann, G. Opelz, C. Harwood and J. McGregor for their significant contributions to this.

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Glossary

Purine salvage pathway

Cells can obtain the purine bases they need to form the precursors of DNA and RNA either by synthesizing them de novo or by recycling from degraded nucleic acids through this pathway.

Myelosuppression

A condition in which the production of blood cells by the bone marrow is significantly reduced. This can result in anaemia, life-threatening infection and spontaneous bleeding.

Km

Derived from enzyme kinetics, Km is the substrate concentration at which an enzymatic reaction proceeds at half-maximal velocity. It is effectively a measure of the affinity of an enzyme for a particular substrate.

Chromophore

That part of a substance that absorbs visible light or, by extension, ultraviolet radiation.

Reactive oxygen species

(ROS). Highly unstable oxygen-containing chemical entities. ROS include oxygen free radicals such as the hydroxyl, peroxyl and superoxide anion radicals and non-free radical forms such as singlet oxygen. Low-level ROS production is an essential component of intracellular signalling.

Fenton-like reactions

Many of the most harmful changes in DNA are caused by hydroxyl radicals. In the Fenton reaction, the relatively innocuous hydrogen peroxide is converted into hydroxyl radicals in a reaction involving iron associated with DNA.

Tm

The temperature at which a DNA double helix dissociates into single strands.

Y-family DNA polymerases

Y-family DNA polymerases have a more open active site than A- and B-family DNA polymerases and can accommodate covalently modified template DNA bases. This allows them to insert nucleotides opposite damaged bases. This 'bypass' mode allows the replication of damaged DNA to continue, although often at a cost to fidelity.

Ulcerative colitis

A form of inflammatory bowel disease in which inflammation affects the large intestine or colon and consists of characteristic ulcers or open sores.

Crohn's disease

A type of inflammatory bowel disease. It is characterized by inflammation across the entire wall of the affected mucosa and can affect any part of the gastrointestinal tract.

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Karran, P., Attard, N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer 8, 24–36 (2008). https://doi.org/10.1038/nrc2292

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