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6-Mercaptopurine Therapy

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Pediatric Inflammatory Bowel Disease

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Abstract

6-Mercaptopurine (6-MP) and its pro-drug azathioprine have proven efficacy in the maintenance of disease remission in children with steroid-dependent Crohn’s disease. However, not all patients respond effectively to therapy, while others are predisposed to drug-induced toxicity; thereby, suggesting that inherent differences in anti-metabolite metabolism may influence clinical responsiveness to therapy. Although genomic (TPMT) and drug metabolite monitoring have been available for greater than a decade, there is more debate than consensus on their application in clinical practice, primarily due to the lack of controlled clinical trials.

Nevertheless, patients with a homozygous recessive TPMT genotype should not be considered candidates for anti-metabolite therapy. Physicians treating patients with a heterozygote genotype should consider a more moderate dosing strategy, while carefully monitoring for potential antimetabolite-induced cytotoxicity. In these patients, 6-MP-metabolite testing may help clinicians monitor immunosuppression and decrease the risk of toxicity. Future prospective clinical trials are necessary in order to develop a therapeutic window of clinical efficacy and toxicity based on the measurement of these drug metabolites.

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References

  1. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500–11.

    Article  PubMed  Google Scholar 

  2. Lichtenstein G, Yan S, Bala M, Hanauer S. Remission in patients with Crohn’s disease associated with improvement in employment and quality of life and decrease in hospitalization and surgeries. Am J Gastroenterol. 2004;99:91–6.

    Article  PubMed  Google Scholar 

  3. Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003;111:1122–4.

    Google Scholar 

  4. Carvalho RS, Mahoney JA, Oliva-Hemker MM, et al. Inherent resistance to 6-thioguanine induced apoptosis correlates with disease activity in children with IBD. Gastroenterology. 2006;130(4):A203.

    Google Scholar 

  5. Pearson DC, May GR, Fick GH, Sutherland SR. Azathioprine and 6-mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med. 1995;122:132–42.

    Google Scholar 

  6. Sands BE, Abreu MT, Ferry GD, et al. Design issues and outcomes in IBD clinical trials. Inflamm Bowel Dis. 2005;11:S22–8.

    Article  PubMed  Google Scholar 

  7. Farrell R, Peppercorn M. Endoscopy in inflammatory bowel disease. In: Sartor R, Sandborn W, editors. Kirsner’s inflammatory bowel diseases. 6th ed. Philadelphia: WB Saunders; 2004. p. 380–98.

    Google Scholar 

  8. Eaden J, Abrams K, Mayberry J. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35.

    Article  PubMed  CAS  Google Scholar 

  9. Actis GC, Pellicano R, Ezio D, Sapino A. Azathioprine, mucosal healing in ulcerative colitis, and the chemoprevention of colitic cancer: a clinical-practice—based forecast. Inflamm Allergy Drug Targets. 2010;9:6–9.

    Article  PubMed  CAS  Google Scholar 

  10. Cuffari C, Hunt S, Bayless TM. Utilization of erythrocyte 6-thioguanine metabolite levels to optimize therapy in IBD. Gut. 2001;48:642–6.

    Article  PubMed  CAS  Google Scholar 

  11. Achar JP, Stevens T, Brzezinski A, Seidner D, Lashner B. 6-Thioguanine levels versus white blood cell counts in guiding 6-mercaptopruine and azathioprine therapy. Am J Gastroenterol. 2000;95:A272.

    Article  Google Scholar 

  12. Lowry PW, Franklin CL, Weaver AL, Szumlanski C, Mays DC, Loftus EV, et al. Leukopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine or balsalazide. Gut. 2001;49:656–64.

    Article  PubMed  CAS  Google Scholar 

  13. Markowitz J, Hyams J, Mack D, Leleiko N, Evans J, Kugathasan S, et al. Pediatric IBD Collaborative Research Group. Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4:1124–9.

    Article  PubMed  CAS  Google Scholar 

  14. Markowitz J, Grancher K, Kohn N, et al. A multi-center trial of 6-mercaptopurine and prednisone therapy in children with newly diagnosed Crohn’s disease. Gastroenterology. 2000;119:895–902.

    Article  PubMed  CAS  Google Scholar 

  15. Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn’s disease: a meta-analysis adjusted for confounding variables. Gastroenterology. 1997;113:1465–73.

    Article  PubMed  CAS  Google Scholar 

  16. Brant SR, Panhuysen CI, Bailey-Wilson JE, et al. Linkage heterogeneity for the IBD1 locus in Crohn’s disease pedigrees by disease onset and severity. Gastroenterology. 2000;119:1483–90.

    Article  PubMed  CAS  Google Scholar 

  17. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCECT I randomized trial. Lancet. 2002;359:1541–9.

    Article  PubMed  CAS  Google Scholar 

  18. Lamireau T, Cezard JP, Dabadie A, et al. Efficacy and tolerance of infliximab in children and adolescents with crohn’s disease. Inflamm Bowel Dis. 2004;10(6):745–50.

    Article  PubMed  Google Scholar 

  19. Hommes D, Baert F, Van Assche G, et al. The ideal management of Crohn’s disease: top down versus step up strategies, a randomized control trial. Gastroenterology. 2006;130(4):A108.

    Google Scholar 

  20. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. SONIC Study Group. Sonic Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383–95.

    Article  PubMed  CAS  Google Scholar 

  21. Panccione R, Ghosh S, Middleton S, et al. Infliximab, azathioprine or infliximab plus azathioprine for treatment of moderate to severe ulcerative colitis: the UC success trial. Gastroenterology. 2011;140(5):A385.

    Google Scholar 

  22. Jones JL, Jr Loftus EV. Lymphoma risk in inflammatory bowel disease: is it the disease or its treatment? Inflamm Bowel Dis. 2007;13(10):1299–307. Review.

    Article  PubMed  Google Scholar 

  23. Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology. 1999;117:761–9.

    Article  PubMed  CAS  Google Scholar 

  24. Cuffari C, Harris M, Bayless TM. 6-mercaptopurine metabolites levels correlate with a favorable clinical response to long-term infliximab therapy. Gastroenterology. 2007;132(4):A234.

    Google Scholar 

  25. Baldassano RN, Han PD, Jeshion WC, et al. Pediatric Crohn’s disease: risk factors for postoperative recurrence. Am J Gastroenterol. 2001;7:2169–76.

    Article  Google Scholar 

  26. Hanauer SB, Korelitz BI, Rutgeerts P, et al. Post-operative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine or placebo: a 2 year trial. Gastroenterology. 2004;127:723–9.

    Article  PubMed  CAS  Google Scholar 

  27. Ewe K, Press AG, Singe CC, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology. 1993;105:367–72.

    PubMed  CAS  Google Scholar 

  28. Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995;37:674–8.

    Article  PubMed  CAS  Google Scholar 

  29. Korelitz BI, Adler DJ, Mendelsohn RA, et al. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol. 1993;88:1198–205.

    PubMed  CAS  Google Scholar 

  30. Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980;302:981–7.

    Article  PubMed  CAS  Google Scholar 

  31. Colonna T, Korelitz BI. The role of leukopenia in 6-mercaptopurine-induced remission of refractory Crohn’s disease. Am J Gastroenterol. 1993;89:362–6.

    Google Scholar 

  32. Present DH, Meltzer SJ, Krumholz MP, et al. 6-mercaptopurine in the management of inflammatory bowel disease: short and long-term toxicity. Ann Intern Med. 1995;111:641–9.

    Google Scholar 

  33. Zimm S, Collins JM, Riccardi R, et al. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered. N Engl J Med. 1983;308:1005–9.

    Article  PubMed  CAS  Google Scholar 

  34. McLeod HL, Relling MV, Liu Q, Pui CH, Evans WE. Polymorphic thiopurine methyl transferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood. 1995;85(7):1897–902.

    PubMed  CAS  Google Scholar 

  35. Alves S, Prata MJ, Ferreira F, Amorim A. Screening of thiopurine methyl s-transferase mutations by horizontal conformation-sensitive gel electrophoresis. Hum Mutat. 2000;15:246–53.

    Article  PubMed  CAS  Google Scholar 

  36. Evans WE, Horner M, Chu YQ, et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirements in a thiopurine methyltransferase deficient child with acute lymphoblastic leukemia. J Pediatr. 1991;119:985–9.

    Article  PubMed  CAS  Google Scholar 

  37. McLeod HL, Krynetski EY, Relling MV, et al. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia. 2000;14:567.

    Article  PubMed  CAS  Google Scholar 

  38. Christie NT, Drake S, Meyn RE. 6-thioguanine induced DNA damage as a determinant of cytotoxicity in cultured hamster ovary cells. Cancer Res. 1986;44:3665–71.

    Google Scholar 

  39. Fairchild CR, Maybaum J, Kennedy KA. Concurrent unilateral chromatid damage and DNA strand breaks in response to 6-thioguanine treatment. Biochem Pharmacol. 1986;35:3533–41.

    Article  PubMed  CAS  Google Scholar 

  40. Weinshilboum RN, Sladek S. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyl transferase activity. Am J Hum Genet. 1980;32:651–62.

    PubMed  CAS  Google Scholar 

  41. Black AJ, McLeod HL, Capell HA. Thiopurine methyl transferase predicts therapy-limitingsever toxicity from azathioprine. Ann Intern Med. 1998;129:716–8.

    PubMed  CAS  Google Scholar 

  42. Conklin L, Cuffari C, Li X. 6-MP transport in lymphocyte: correlation with toxicity. J Dig Dis. 2012;13(2):82–93.

    Article  PubMed  CAS  Google Scholar 

  43. Cuffari C, Theoret Y, Latour S, et al. 6-mercaptopurine metabolism in Crohn’s disease: correlation with efficacy and toxicity. Gut. 1996;39:401–6.

    Article  PubMed  CAS  Google Scholar 

  44. Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Theoret Y, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705–13.

    Article  PubMed  CAS  Google Scholar 

  45. Gupta P, Gokhlae R, Kirschner BS. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2001;33:450–4.

    Article  PubMed  CAS  Google Scholar 

  46. Belaiche J, Desager JP, Horsman Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn’s disease. Scand J Gastroenterol. 2001;36:71–6.

    Article  PubMed  CAS  Google Scholar 

  47. Goldenberg BA, Rawsthorne P, Berstein CN. The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol. 2004;99:1744–8.

    Article  PubMed  CAS  Google Scholar 

  48. Cuffari C, Dassoupolus T, Bayless TM. Thiopurine methyl-transferase activity influences clinical response to azathioprine therapy in patients with IBD. Clin Gastroenterol Hepato. 2004;2:410–7.

    Article  CAS  Google Scholar 

  49. Kaskas BA, Louis E, Hinderof U, et al. Safe treatment of thiopurine S-transferase deficient Crohn’s disease patients with azathioprine. Gut. 2003;52:140–2.

    Article  PubMed  CAS  Google Scholar 

  50. Dubinsky MC, Yang H, Hassard PV, Seidman EG, Kam LY, Abreu MT, et al. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology. 2002;122:904–15.

    Article  PubMed  CAS  Google Scholar 

  51. Sparrow MP, Hande SA, Friedman S, et al. Allopurinol safely and effectively optimizes thioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther. 2005;22:441–6.

    Article  PubMed  CAS  Google Scholar 

  52. Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 2000;118(6):1025–30.

    Article  PubMed  CAS  Google Scholar 

  53. Bo J, Schroder H, Kristinsson J. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer. 1999;86:1080–6.

    Article  PubMed  CAS  Google Scholar 

  54. Garza A, Sninsky CA. Changes in red cell mean corpuscular volume (MCV) during azathioprine or 6-mercaptopurine therapy for Crohn’s disease may indicate optimal dose titration. Gastroenterology. 2001;120:A3166.

    Google Scholar 

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Pediatrics, The Johns Hopkins Hospital, 600N. Wolfe St. Brady 308, Baltimore, MD, 21287, USA

    Carmen Cuffari MD

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  1. Carmen Cuffari MD
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Correspondence to Carmen Cuffari MD .

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Editors and Affiliations

  1. Perelman School of Medicine, The Children’s Hospital of Philadelphia, University of Pennsylvania, 34th St. & Civic Ctr. Blvd., Philadelphia, 19104, Pennsylvania, USA

    Petar Mamula

  2. School of Medicine--Greenville, Pediatric Gastroenterology & Nutrition, University of South Carolina, 200 Patewood Drive, Suite A-140, Greenville, 29615, South Carolina, USA

    Jonathan E. Markowitz

  3. Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, 34th St. & Civic Ctr. Blvd., Philadelphia, 19104, Pennsylvania, USA

    Robert N. Baldassano

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Cuffari, C. (2013). 6-Mercaptopurine Therapy. In: Mamula, P., Markowitz, J., Baldassano, R. (eds) Pediatric Inflammatory Bowel Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5061-0_31

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  • DOI: https://doi.org/10.1007/978-1-4614-5061-0_31

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