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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Flowers, C. R. & Melmon, K. L. Clinical investigators as critical determinants in pharmaceutical innovation. Nature Med. 3, 136–143 (1997).
Azathioprine. IARC Monographs 26 (Suppl. 7), 119 (1987).
Smith, C. et al. AIDS-related malignancies. Ann. Med. 30, 323–344 (1998).
Grulich, A. E., van Leeuwen, M. T., Falster, M. O. & Vajdic, C. M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370, 59–67 (2007).
Harwood, C. A. et al. Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin. Br. J. Dermatol. 150, 949–957 (2004).
Clarke, D. A. et al. 6-Mercaptopurine: effects in mouse sarcoma 180 and in normal animals. Cancer Res. 13, 593–604 (1953).
Burchenal, J. H. et al. Clinical evaluation of a new metabolite, 6-mercaptopurine, in the treatment of leukaemia and allied diseases. Blood 8, 965–999 (1953).
Remuzzi, G. et al. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. Lancet 364, 503–512 (2004).
Brennan, D. C. & Koch, M. J. Is mycophenolate mofetil really necessary in renal transplantation? A review of the MYSS follow-up study. Nature Clin. Pract. 3, 602–603 (2007).
Taylor, A. L., Watson, C. J. E. & Bradley, J. A. Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit. Rev. Oncol. Haematol. 56, 23–46 (2005).
Bean, R. H. D. Treatment of ulcerative colitis with antimetabolites. Br. Med. J. 1, 1081–1084 (1966).
Connell, W. R., Kamm, M. A., Ritchie, J. K. & Lennard-Jones, J. E. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 34, 1081–1085 (1993).
Aarbakke, J., Janka-Schaub, G. & Elion, G. B. Thiopurine biology and pharmacology. Trends Pharmacol. Sci. 18, 3–8 (1997).
Fotoohi, A. K., Lindquist, M., Peterson, C. & Albertoni, F. Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines. Biochem. Biophys. Res. Commun. 343, 208–215 (2006).
Wang, L. & Weinshilboum, R. Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions. Oncogene 25, 1629–1638 (2006). An excellent review of the properties, regulation and genetics of TPMT and the implications of this information for clinical practice.
Krynetski, E. & Evans, W. E. Drug methylation in cancer therapy: lessons from the TPMT polymorphism. Oncogene 22, 7403–7413 (2003).
Ranjard, L., Prigent-Combaret, C., Nazaret, S. & Cournoyer, B. Methylation of inorganic and organic selenium by the bacterial thiopurine methyltransferase. J. Bacteriol. 184, 3146–3149 (2002).
Krynetski, E. Y., Krynetskaia, N. F., Yanishevski, Y. & Evans, W. E. Methylation of mercaptopurine, thioguanine, and their nucleotide metabolites by heterologously expressed human thiopurine S-methyltransferase. Mol. Pharmacol. 47, 1141–1147 (1995).
Marshall, E. Preventing toxicity with a gene test. Science 302, 588–590 (2003).
Yoshida, S., Yamada, M., Masaki, S. & Saneyoshi, M. Utilization of 2′-deoxy-6-thioguanosine 5′-triphosphate in DNA synthesis in vitro by DNA polymerase α from calf thymus. Cancer Res. 39, 3955–3958 (1979).
Ling, Y. H., Nelson, J. A., Cheng, Y. C., Anderson, R. S. & Beattie, K. L. 2′-Deoxy-6-thioguanosine 5′-triphosphate as a substrate for purified human DNA polymerases and calf thymus terminal deoxynucleotidyltransferase in vitro. Mol. Pharmacol. 40, 508–514 (1991).
Zhang, X. et al. Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light. DNA Repair 6, 344–354 (2006).
Rappaport, H. P. Replication of the base pair 6-thioguanine/5-methyl-2-pyrimidone with the large Klenow fragment of Escherichia coli DNA polymerase I. Biochemistry 32, 3047–3057 (1993).
Tidd, D. M. & Paterson, A. R. P. Distinction between inhibition of purine nucleotide synthesis and the delayed cytotoxic reaction of 6-mercaptopurine. Cancer Res. 34, 733–737 (1974).
Tan, Y., Berry, S. E., Desai, A. B. & Kinsella, T. J. DNA mismatch repair (MMR) mediates 6-thioguanine genotoxicity by introducing single-strand breaks to signal a G2–M arrest in MMR-proficient RKO cells. Clin. Cancer Res. 9, 2327–2334 (2003).
Roberts, J. J., Pascoe, J. M., Plant, J. E., Sturrock, J. E. & Crathorn, A. R. Quantitative aspects of the repair of alkylated DNA in cultured mammalian cells. I. The effect on HeLa and Chinese hamster cell survival of alkylation of cellular macromolecules. Chem. Biol. Interact. 3, 29–47 (1971). The first in a series of detailed studies of the effects of methylating agents on the cell cycle and on survival. These papers were influential in the development of the 'futile processing' model of mismatch repair intervention at DNA damage.
Zhukovskaya, N., Branch, P., Aquilina, G. & Karran, P. DNA replication arrest and tolerance to DNA methylation damage. Carcinogenesis 15, 2189–2194 (1994).
Karran, P. & Bignami, M. DNA damage tolerance, mismatch repair and genome instability. BioEssays 16, 833–839 (1994).
Aquilina, G. et al. Tolerance to O6-methylguanine and 6-thioguanine cytotoxic effects: a cross-resistant phenotype in N-methylnitrosourea-resistant Chinese hamster ovary cells. Cancer Res. 50, 4248–4253 (1990). This paper makes the important connection between resistance to methylating agents and to thiopurines and suggests that these share a common underlying mechanism.
Koi, M. et al. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N′-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res. 54, 4308–4312 (1994).
Karran, P. & Marinus, M. G. Mismatch correction at O6-methylguanine residues in E. coli DNA. Nature 296, 868–869 (1982). Establishes the connection between defective mismatch repair and resistance to killing by DNA O6-methylguanine in bacteria.
Swann, P. F. Why do O6-alkylguanine and O4-alkylthymine miscode? The relationship between the structure of DNA containing O6-alkylguanine and O4-alkylthymine and the mutagenic properties of these bases. Mutat. Res. 233, 81–94 (1990).
Hawn, M. T. et al. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res. 55, 3721–3725 (1995).
Stojic, L. et al. Mismatch repair-dependent G2 checkpoint induced by low doses of SN1-type methylating agents requires the ATR kinase. Genes Dev. 18, 1331–1344 (2004). The first careful examination of the molecular signalling events downstream of mismatch repair processing of DNA methylation damage.
Yoshioka, K., Yoshioka, Y. & Hsieh, P. ATR kinase activation mediated by MutSα and MutLα in response to cytotoxic O6-methylguanine adducts. Mol. Cell 22, 501–510 (2006).
Adamson, A. W., Kim, W.-J., Shangary, S., Baskaran, R. & Brown, K. D. ATM is activated in response to N-methyl-N′-nitro-N-nitrosoguanidine-induced DNA alkylation. J. Biol. Chem. 277, 38222–38229 (2002).
Stojic, L., Cejka, P. & Jiricny, J. High doses of SN1 type methylating agents activate DNA damage signaling cascades that are largely independent of mismatch repair. Cell Cycle 4, 473–477 (2005).
Zou, L. & Elledge, S. J. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542–1548 (2003).
York, S. J. & Modrich, P. Mismatch repair-dependent iterative excision at irreparable O6-methylguanine lesions in human nuclear extracts. J. Biol. Chem. 281, 22674–22683 (2006). This paper provides the first direct biochemical evidence in support of the futile processing cycle model of methylation tolerance.
Berardini, M., Mazurek, A. & Fishel, R. The effect of O6-methylguanine DNA adducts on the adenosine nucleotide switch functions of hMSH2–hMSH6 and hMSH2–hMSH3. J. Biol. Chem. 275, 27851–27857 (2000).
Kaina, B., Ziouta, A., Ochs, K. & Coquerelle, T. Chromosomal instability, reproductive cell death and apoptosis induced by O6-methylguanine in Mex−, Mex+ and methylation-tolerant mismatch repair compromised cells: facts and models. Mutat. Res. 381, 227–241 (1997).
Vernole, P., Pepponi, R. & d'Atri, S. Role of mismatch repair in the induction of chromosomal aberrations and sister chromatid exchanges in cells treated with different chemotherapeutic agents Cancer Chemother. Pharmacol. 52, 185–192 (2003).
Abdel-Rahman, W. M., Mecklin, J. P. & Peltomäki, P. The genetics of HNPCC: application to diagnosis and screening. Crit. Rev. Oncol. Hematol. 58, 208–220 (2006).
Swann, P. F. et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science 273, 1109–1111 (1996). The first demonstration that the chemically favoured S-methylation of DNA 6-TG was important for its interaction with mismatch repair.
Xu, Y.-Z., Zheng, Q. & Swann, P. F. Synthesis by post-synthetic substitution of oligomers containing guanine modified at the 6-position with S- N-, O-derivatives. Tetrahedron 48, 1729–1742 (1992).
Rydberg, B. & Lindahl, T. Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction. EMBO J. 1, 211–216 (1982).
Bodell, W. J. Investigation of 6-thiodeoxyguanosine alkylation products and their role in the potentiation of BCNU cytotoxicity. IARC Sci. Pub. 70, 147–154 (1986).
Branch, P., Aquilina, G., Bignami, M. & Karran, P. Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage. Nature 362, 652–654 (1993).
Offman, J. et al. Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation. Blood 104, 822–828 (2004).
Fotoohi, A. K., Lindquist, M., Peterson, C. & Albertoni, F. Impaired transport as a mechanism of resistance to thiopurines in human T-lymphoblastic leukemia cells. Nucleosides Nucleotides Nucleic Acids 25, 1039–1044 (2006).
Krynetski, E. Y., Krynetskaia, N. F., Gallo, A. E., Murti, K. G. & Evans, W. E. A novel protein complex distinct from mismatch repair binds thioguanylated DNA. Mol. Pharmacol. 59, 367–374 (2001).
Krynetski, E. Y., Krynetskaia, N. F., Bianchi, M. E. & Evans, W. E. A nuclear protein complex containing high mobility group proteins B1 and B2, heat shock cognate protein 70, ERp60, and glyceraldehyde-3-phosphate dehydrogenase is involved in the cytotoxic response to DNA modified by incorporation of anticancer nucleoside analogs. Cancer Res. 63, 100–106 (2003).
Tay, B. S., Lilley, R. M., Murray, A. W. & Atkinson, M. R. Inhibition of phosphoribosyl pyrophosphate amidotransferase from Ehrlich ascites-tumour cells by thiopurine nucleotides. Biochem. Pharmacol. 18, 936–938 (1969).
Relling, M. V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J. Natl Cancer Inst. 91, 2001–2008 (1999).
Lennard, L. Therapeutic drug monitoring of antimetabolic cytotoxic drugs. Br. J. Clin. Pharmac. 47, 131–143 (1999).
Lennard, L., van Loon, J. A. & Weinshilboum, R. M. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin. Pharmacol. Ther. 46, 149–154 (1989). One of several important papers by these authors drawing attention to the importance of thioguanine nucleotides and thiopurine S -methyltransferase levels in myelotoxicity following thiopurine treatment.
Schütz, E., Gummert, J., Armstrong, V. W., Mohr, F. W. & Oellerich, M. Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation. Eur. J. Clin. Chem. Clin. Biochem. 34, 199–205 (1996).
Allison, A. C. & Eugui, E. M. Mycophenolate mofetil and its mechanism of action. Immunopharmacology 47, 85–118 (2000).
Brimmel, M., Mendiola, R., Mangion, J. & Packham, G. BAX frameshift mutations in cell lines derived from human haematopoietic malignancies are associated with resistance to apoptosis and microsatellite instability. Oncogene 16, 1803–1812 (1998).
Taverna, P., Liu, L., Hanson, A. J., Monks, A. & Gerson, S. L. Characterization of MLH1 and MSH2 DNA mismatch repair proteins in cell lines of the NCI anticancer drug screen. Cancer Chemother. Pharmacol. 46, 507–516 (2000).
Cejka, P. et al. Methylation-induced G2/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO J. 22, 2245–2254 (2003).
Matheson, E. C. & Hall, A. G. Assessment of mismatch repair function in leukaemic cell lines and blasts from children with acute lymphoblastic leukaemia. Carcinogenesis 24, 31–38 (2003).
Karran, P. Mechanisms of tolerance to DNA damaging therapeutic drugs. Carcinogenesis 22, 1931–1937 (2001).
Dervieux, T. et al. Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res. 61, 5810–5816 (2001).
Dervieux, T. et al. De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo. Blood 100, 1240–1247 (2002).
Hartford, C. et al. Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Cancer Res. 67, 4965–4972 (2007).
Bruls, W. A., Slaper, H., van der Leun, J. C. & Berrens, L. Transmission of human epidermis and stratum corneum as a function of thickness in the ultraviolet and visible wavelengths. Photochem. Photobiol. 40, 485–494 (1984).
International Programme on Chemical Safety. Environmental health criteria 160: ultraviolet radiation. International Programme on Chemical Safety [online], (1994).
O'Donovan, P. et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 309, 1871–1874 (2005). The authors identified a new product of the photochemical reactions of DNA 6-thioguanine and demonstrated that these reactions might be important in patients on azathioprine.
Hemmens, V. J. & Moore, D. E. Photochemical sensitization by azathioprine and its metabolites. I. 6-Mercaptopurine. Photochem. Photobiol. 43, 247–255 (1986).
Cadet, J., Sage, E. & Douki, T. Ultraviolet radiation-mediated damage to cellular DNA. Mutat. Res. 571, 3–17 (2005).
Shen, H. R., Spikes, J. D., Kopecekova, P. & Kopecek, J. Photodynamic crosslinking of proteins. II. Photocrosslinking of a model protein-ribonuclease A. J. Photochem. Photobiol. B 35, 213–219 (1996).
Au, V. & Madison, S. A. Effects of singlet oxygen on the extracellular matrix protein collagen: oxidation of the collagen crosslink histidinohydroxylysinonorleucine and histidine. Arch. Biochem. Biophys. 384, 133–142 (2000).
Montaner, B. et al. Reactive oxygen-mediated damage to a human DNA replication and repair protein EMBO Rep. 8, 1074–1079 (2007).
Cadet, J., Douki, T., Gasparutto, D. & Ravanat, J.-L. Oxidative damage to DNA: formation, measurement and biochemical features. Mutat. Res. 531, 5–23 (2003).
Lehmann, A. R. Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett. 579, 873–876 (2005).
Spector, A. Oxidative stress-induced cataract: mechanism of action. FASEB J. 9, 1173–1182 (1995).
Wondrak, G. T., Roberts, M. J., Jacobson, M. K. & Jacobson, E. L. Photosensitized growth inhibition of cultured human skin cells: mechanism and suppression of oxidative stress from solar irradiation of glycated proteins. J. Invest. Dermatol. 119, 489–498 (2002).
Balasubramanian, D., Du, X. & Zigler, J. S. The reactions of singlet oxygen with proteins, with special reference to crystallins. Photochem. Photobiol. 52, 761–768 (1990).
Thomsen, J. B. et al. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells. Cancer 86, 1080–1086 (1999).
Relling, M. V. et al. Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia. Leukemia 12, 346–352 (1998).
Opelz, G. & Henderson, R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 342, 1514–1516 (1993).
Euvrard, S. et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J. Am. Acad. Dermatol. 33, 222–229 (1995). This article reviews the incidences of the most common types of skin cancer in transplant patients.
Bordea, C. et al. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation 77, 574–579 (2004).
Penn, I. Cancer in the immunosuppressed organ recipient. Transplant Proc. 23, 1771–1772 (1991).
Euvrard, S., Kanitakis, J. & Claudy, A. Skin cancers after organ transplantation. N. Engl. J. Med. 348, 1681–1691 (2003).
Mullen, D. L., Silverberg, S. G., Penn, I. & Hammond, W. S. Squamous cell carcinoma of the skin and lip in renal homograft recipients. Cancer 37, 729–734 (1976).
Penn, I. The problem of cancer in transplant patients: an overview. Transplant. Sci. 4, 23–32 (1994).
Young, A. R. & Walker, S. L. Effects of solar simulated radiation on the human immune system: influence of phototypes and wavebands. Exp. Dermatol. 11 (Suppl. 1), 17–19 (2002).
Hanneman, K. K., Cooper, K. D. & Baron, E. D. Ultraviolet immunosuppression: mechanisms and consequences. Dermatol. Clin. 24, 19–25 (2006).
Warren, D. J., Andersen, A. & Slordal, L. Quantitation of 6-thioguanine residues in peripheral blood leukocyte DNA obtained from patients receiving 6-mercaptopurine-based maintenance therapy. Cancer Res. 55, 1670–1674 (1995).
Cuffari, C., Li, D. Y., Mahoney, J., Barnes, J. Y. & Bayless, T. M. Peripheral blood mononuclear cell DNA 6-thioguanine metabolite levels correlate with decreased interferon-γ production in patients with Crohn's disease on AZA therapy. Dig. Dis. Sci. 49, 133–137 (2004).
Baumgart, D. C. & Carding, S. R. Inflammatory bowel disease: cause and immunobiology. Lancet 369, 1627–1640 (2007).
Bernstein, C. N., Blanchard, J. F., Kliewer, E. & Wajda, A. Cancer risk in patients with inflammatory bowel disease. Cancer 91, 854–862 (2001).
Masunaga, Y. et al. Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease. Ann. Pharmacother. 41, 21–28 (2007).
Seril, D. N., Liao, J., Yang, G.-Y. & Yang, C. S. Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24, 353–362 (2003).
Lee, D.-H., Esworthy, R. S., Chu, C., Pfeifer, G. P. & Chu, F.-F. Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Cancer Res. 66, 9845–9851 (2006).
Weinshilboum, R. M. & Sladek, S. L. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 32, 651–662 (1980).
Naughton, M. A., Battaglia, E., O'Brien, S., Walport, M. J. & Botto, M. Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. Rheumatology 38, 640–644 (1999).
Savani, F. A., Prosser, C., Bailey, R. J., Jacobs, P. & Fedorak, R. N. Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost and adverse events. Can. J. Gastroenterol. 19, 147–151 (2005).
Dubinsky, M. C. et al. A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Am. J. Gastroenterol. 100, 2239–2247 (2005).
Anstev, A. V., Wakelin, S. & Reynolds, N. J. Guidelines for prescribing azathioprine in dermatology. Br. J. Dermatol. 151, 1123–1132 (2004).
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.
Author information
Authors and Affiliations
Corresponding author
Related links
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.
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1038/nrc2292
This article is cited by
-
An analysis pipeline for understanding 6-thioguanine effects on a mouse tumour genome
Cancer Immunology, Immunotherapy (2024)
-
Nanotechnology in leukemia: diagnosis, efficient-targeted drug delivery, and clinical trials
European Journal of Medical Research (2023)
-
Targeting DNA polymerase β elicits synthetic lethality with mismatch repair deficiency in acute lymphoblastic leukemia
Leukemia (2023)
-
Hypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas
Nature Communications (2023)
-
Cumulative exposure to tacrolimus during early period after liver transplantation does not affect the recurrence of hepatocellular carcinoma
Scientific Reports (2023)