Skip to main content
SpringerLink
Log in

Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL.

Methods

Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6 months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient’s files.

Results

Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24 weeks of maintenance therapy.

Conclusions

The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Weinshilboum RM, Sladek SL (1980) Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32:651–662

    PubMed  CAS  Google Scholar 

  2. Zhou S (2006) Clinical pharmacogenomics of thiopurine S-methyltransferase. Curr Clin Pharmacol 1:119–128

    PubMed  CAS  Google Scholar 

  3. Pieters R, Carroll WL (2010) Biology and treatment of acute lymphoblastic leukemia. Hematol Oncol Clin N Am 24:1–18

    Article  Google Scholar 

  4. McLeod HL, Lin JS, Scott EP, Pui CH, Evans WE (1994) Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 55:15–20

    Article  PubMed  CAS  Google Scholar 

  5. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV, Evans WE (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathiopurine and mercaptopurine intolerance. Ann Intern Med 126:608–614

    PubMed  CAS  Google Scholar 

  6. Higgs JE, Payne K, Roberts C, Newman WG (2010) Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications. Pharmacogenomics 11:177–188

    Article  PubMed  CAS  Google Scholar 

  7. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001–2008

    Article  PubMed  CAS  Google Scholar 

  8. Ujiie S, Sasaki T, Mizugaki M, Ishikawa M, Hiratsuka M (2008) Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT*2–*24). Pharmacogenet Genomics 18:887–893

    Article  PubMed  CAS  Google Scholar 

  9. Rutherford K, Daggett V (2008) Four human thiopurine s-methyltransferase alleles severely affect protein structure and dynamics. J Mol Biol 379:803–814

    Article  PubMed  CAS  Google Scholar 

  10. Evans WE (2002) Comprehensive assessment of thiopurine S-methyltransferase (TPMT) alleles in three ethnic populations. J Pediatr Hematol Oncol 24:335–336

    Article  PubMed  Google Scholar 

  11. Ganiere-Monteil C, Medard Y, Lejus C, Bruneau B, Pineau A, Fenneteau O, Bourin M, Jacqz-Aigrain E (2004) Phenotype, genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Eur J Clin Pharmacol 60:89–96

    Article  PubMed  CAS  Google Scholar 

  12. Serpe L, Calvo PL, Muntoni E, D’Antico S, Giaccone M, Avagnina A, Baldi M, Barbera C, Curti F, Pera A et al (2009) Thiopurine S-methyltransferase pharmacogenetics in a large-scale healthy Italian-Caucasian population: differences in enzyme activity. Pharmacogenomics 10:1753–1765

    Article  PubMed  CAS  Google Scholar 

  13. Gisbert JP, Gomollon F, Cara C, Luna M, Gonzalez-Lama Y, Pajares JM, Mate J, Guijarro LG (2007) Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. Dig Dis Sci 52:1262–1269

    Article  PubMed  CAS  Google Scholar 

  14. Dokmanovic L, Urosevic J, Janic D, Jovanovic N, Petrucev B, Tosic N, Pavlovic S (2006) Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia. Ther Drug Monit 28:800–806

    Article  PubMed  CAS  Google Scholar 

  15. Efrati E, Adler L, Krivoy N, Sprecher E (2009) Distribution of TPMT risk alleles for thiopurine [correction of thioupurine] toxicity in the Israeli population. Eur J Clin Pharmacol 65:257–262

    Article  PubMed  CAS  Google Scholar 

  16. Kham SK, Soh CK, Liu TC, Chan YH, Ariffin H, Tan PL, Yeoh AE (2008) Thiopurine S-methyltransferase activity in three major Asian populations: a population-based study in Singapore. Eur J Clin Pharmacol 64:373–379

    Article  PubMed  CAS  Google Scholar 

  17. Samochatova EV, Chupova NV, Rudneva A, Makarova O, Nasedkina TV, Fedorova OE, Glotov AS, Kozhekbaeva Z, Maiorova OA, Roumyantsev AG et al (2009) TPMT genetic variations in populations of the Russian Federation. Pediatr Blood Cancer 52:203–208

    Article  PubMed  Google Scholar 

  18. Ando M, Ando Y, Hasegawa Y, Sekido Y, Shimokata K, Horibe K (2001) Genetic polymorphisms of thiopurine S-methyltransferase and 6-mercaptopurine toxicity in Japanese children with acute lymphoblastic leukemia. Pharmacogenetics 11:269–273

    Article  PubMed  CAS  Google Scholar 

  19. Kapoor G, Maitra A, Brahmachari S, Brahmachari V (2009) Application of SNaPshot for analysis of thiopurine methyltransferase gene polymorphisms. Indian J Med Res 129:500–505

    PubMed  CAS  Google Scholar 

  20. Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL (1999) Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet 8:367–370

    Article  PubMed  CAS  Google Scholar 

  21. Kaya Z, Gursel T, Bakkaloglu SA, Kocak U, Atasever T, Oktar SO (2007) Evaluation of renal function in Turkish children receiving BFM-95 therapy for acute lymphoblastic leukemia. Pediatr Hematol Oncol 24:257–267

    Article  PubMed  Google Scholar 

  22. Tumer TB, Ulusoy G, Adali O, Sahin G, Gozdasoglu S, Arinc E (2007) The low frequency of defective TPMT alleles in Turkish population: a study on pediatric patients with acute lymphoblastic leukemia. Am J Hematol 82:906–910

    Article  PubMed  CAS  Google Scholar 

  23. Ada AO, Suzen HS, Iscan M (2007) Polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1 in a male Turkish population. Int J Toxicol 26:41–46

    Article  PubMed  CAS  Google Scholar 

  24. Aydin M, Hatirnaz O, Erensoy N, Ozbek U (2005) CYP2D6 and CYP1A1 mutations in the Turkish population. Cell Biochem Funct 23:133–135

    Article  PubMed  CAS  Google Scholar 

  25. Lennard L, Welch JC, Lilleyman JS (1997) Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity. Br J Clin Pharmacol 44:455–461

    Article  PubMed  CAS  Google Scholar 

  26. Stanulla M, Schaeffeler E, Flohr T, Cario G, Schrauder A, Zimmermann M, Welte K, Ludwig WD, Bartram CR, Zanger UM, Eichelbaum M, Schrappe M, Schwab M (2005) Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 293:1485–1489

    Article  PubMed  CAS  Google Scholar 

  27. Pui CH, Relling MV, Evans WE (2002) Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia. Best Pract Res Clin Haematol 15:741–756

    Article  PubMed  CAS  Google Scholar 

  28. Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE (1999) Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93:2817–2823

    PubMed  CAS  Google Scholar 

  29. Tani C, Mosca M, Colucci R, Gori G, d’Ascanio A, Ghisu N, Fornai M, Di Paolo A, Blandizzi C, Del Tacca M et al (2009) Genetic polymorphisms of thiopurine S-methyltransferase in a cohort of patients with systemic autoimmune diseases. Clin Exp Rheumatol 27:321–324

    PubMed  CAS  Google Scholar 

  30. Gisbert JP, Nino P, Rodrigo L, Cara C, Guijarro LG (2006) Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients. Am J Gastroenterol 101:2769–2776

    Article  PubMed  CAS  Google Scholar 

  31. Song DK, Zhao J, Zhang LR (2006) TPMT genotype and its clinical implication in renal transplant recipients with azathiopurine treatment. J Clin Pharm Ther 31:627–635

    Article  PubMed  CAS  Google Scholar 

  32. Rees JK, Gray RG (1990) Remission induction and post remission therapy in acute myelogenous leukemia. Haematol Blood Transfus 33:243–248

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by Grant No. 01/2008-38 from Gazi University.

Author information

Authors and Affiliations

  1. Pediatric Hematology Unit of the Department of Pediatrics, Medical School of Gazi University, Ankara, Turkey

    Meryem Albayrak, Uljan Konyssova, Zuhre Kaya, Turkiz Gursel & Ulker Kocak

  2. Department of Clinical Genetics, Medical School of Gazi University, Ankara, Turkey

    Sezen Guntekin & E. Ferda Percin

  3. Sokullu Mehmet Paşa Cad. 92/6, Çankaya, Ankara, Turkey

    Meryem Albayrak

Authors
  1. Meryem Albayrak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Uljan Konyssova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zuhre Kaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Turkiz Gursel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sezen Guntekin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Ferda Percin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ulker Kocak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meryem Albayrak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Albayrak, M., Konyssova, U., Kaya, Z. et al. Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 68, 1155–1159 (2011). https://doi.org/10.1007/s00280-011-1599-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1599-7

Keywords

Search

Navigation