DOI QR코드

DOI QR Code

Association Between Polymorphisms of Dihydrofolate Reductase and Gamma Glutamyl Hydrolase Genes and Toxicity of High Dose Methotrexate in Children with Acute Lymphoblastic Leukemia

  • Koomdee, Napatrupron (Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Hongeng, Suradej (Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Apibal, Suntaree (Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University) ;
  • Pakakasama, Samart (Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University)
  • 발행 : 2012.07.31

초록

Methotrexate (MTX) is an important drug for the treatment of childhood acute lymphoblastic leukemia (ALL). However, related toxicity occurs in many organs which may cause interruption of treatment, morbidity, and mortality. Single nucleotide polymorphisms (SNPs) of dihydrofolate reductase (DHFR) and gamma glutamyl hydrolase (GGH) are known to alter their enzymatic activity and thus affect the metabolism of MTX and influence the effectiveness. Therefore, we hypothesized that genetic variations of DHFR and GGH genes may influence the risk of toxicity after high dose MTX. The study population comprised of 105 children with ALL who were treated according to the modified St Jude Total XV protocol. The patients received 2.5 or $5g/m^2$ of MTX for 5 doses during the consolidation phase. Genotyping of DHFR 829C>T and GGH-401C>T was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The GGH-401CT and TT genotypes were associated with increased risk of leukopenia and thrombocytopenia after high dose MTX (OR 2.97, 95%CI; 1.24-7.13 and OR 4.02, 95%CI; 1.58-10.26). DHFR 829C>T was not associated with toxicity. In conclusion, the GGH-401CT and TT genotypes were found to increase the risk of severe leukopenia and thrombocytopenia after exposure to high dose MTX for childhood ALL therapy.

키워드

참고문헌

  1. Chabner BA, Allegra CJ, Curt GA, et al (1985). Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest, 76, 907-12. https://doi.org/10.1172/JCI112088
  2. Chave KJ, Auger IE, Galivan J, et al (2000). Molecular modeling and site-directed mutagenesis define the catalytic motif in human gamma -glutamyl hydrolase. J Biol Chem, 275, 40365-70. https://doi.org/10.1074/jbc.M007908200
  3. Chave KJ, Ryan TJ, Chmura SE, et al (2003). Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. Gene, 319, 167-75. https://doi.org/10.1016/S0378-1119(03)00807-2
  4. Chen MJ, Shimada T, Moulton AD, et al (1984). The functional human dihydrofolate reductase gene. J Biol Chem, 259, 3933-43.
  5. Dervieux T, Greenstein N, Kremer J (2006). Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum, 54, 3095-103. https://doi.org/10.1002/art.22129
  6. Dervieux T, Kremer J, Lein DO, et al (2004). Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics, 14, 733-9. https://doi.org/10.1097/00008571-200411000-00004
  7. Evans WE, Relling MV (1999). Pharmacogenomics: translating functional genomics into rational therapeutics. Science, 286, 487-91. https://doi.org/10.1126/science.286.5439.487
  8. Fotoohi AK, Albertioni F (2008). Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells. Leuk Lymphoma, 49, 410-26. https://doi.org/10.1080/10428190701824569
  9. Galivan J, Ryan T, Rhee M, et al (1999). Glutamyl hydrolase: properties and pharmacologic impact. Semin Oncol, 26, 33-7.
  10. Garcia-Bournissen F, Moghrabi A, Krajinovic M (2007). Therapeutic responses in childhood acute lymphoblastic leukemia (ALL) and haplotypes of gamma glutamyl hydrolase (GGH) gene. Leuk Res, 31, 1023-5. https://doi.org/10.1016/j.leukres.2006.08.007
  11. Genestier L, Paillot R, Quemeneur L, et al (2000). Mechanisms of action of methotrexate. Immunopharmacology, 47, 247-57. https://doi.org/10.1016/S0162-3109(00)00189-2
  12. Gorlick R, Goker E, Trippett T, et al (1996). Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med, 335, 1041-8. https://doi.org/10.1056/NEJM199610033351408
  13. Goto Y, Yue L, Yokoi A, et al (2001). A novel single-nucleotide polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res, 7, 1952-6.
  14. Morandi C, Masters JN, Mottes M, et al (1982). Multiple forms of human dihydrofolate reductase messenger RNA. Cloning and expression in Escherichia coli of their DNA coding sequence. J Mol Biol, 156, 583-607. https://doi.org/10.1016/0022-2836(82)90268-6
  15. Organista-Nava J, Gomez-Gomez Y, Saavedra-Herrera MV, et al (2010). Polymorphisms of the gamma-glutamyl hydrolase gene and risk of relapse to acute lymphoblastic leukemia in Mexico. Leuk Res, 34, 728-32. https://doi.org/10.1016/j.leukres.2009.11.027
  16. Panetta JC, Wall A, Pui CH, et al (2002). Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity. Clin Cancer Res, 8, 2423-9.
  17. Relling MV, Dervieux T (2001). Pharmacogenetics and cancer therapy. Nat Rev Cancer, 1, 99-108. https://doi.org/10.1038/35101056
  18. Rhee MS, Lindau-Shepard B, Chave KJ, et al (1998). Characterization of human cellular gamma-glutamyl hydrolase. Mol Pharmacol, 53, 1040-6.
  19. St Jude Children's Research Hospital (2005). St. Jude Total therapy XV: St Jude Children's Research Hospital, National Institutes of Health (NTH).
  20. US Department of Health and Human Services (2009). Common terminology criteria for adverse events version 4.0 (CTCAE): U.S. Department of Health and Human services, National Institutes of Health, National Cancer Institute.
  21. Yao R, Schneider E, Ryan TJ, et al (1996). Human gamma-glutamyl hydrolase: cloning and characterization of the enzyme expressed in vitro. Proc Natl Acad Sci USA, 93, 10134-8. https://doi.org/10.1073/pnas.93.19.10134
  22. Yin D, Chave KJ, Macaluso CR, et al (1999). Structural organization of the human gamma-glutamyl hydrolase gene. Gene, 238, 463-70. https://doi.org/10.1016/S0378-1119(99)00362-5

피인용 문헌

  1. γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate vol.109, pp.8, 2013, https://doi.org/10.1038/bjc.2013.579
  2. Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia vol.74, pp.2, 2014, https://doi.org/10.1007/s00280-014-2507-8
  3. γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells vol.10, pp.1, 2015, https://doi.org/10.1007/s12263-014-0444-0
  4. Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL vol.36, pp.7, 2015, https://doi.org/10.1007/s13277-015-3602-0
  5. Dihydrofolate Reductase Genetic Polymorphisms Affect Methotrexate Dose Requirements in Pediatric Patients With Acute Lymphoblastic Leukemia on Maintenance Therapy vol.39, pp.8, 2017, https://doi.org/10.1097/MPH.0000000000000908
  6. Genetic markers in methotrexate treatments pp.1473-1150, 2018, https://doi.org/10.1038/s41397-018-0047-z
  7. SNPs affecting the clinical outcomes of regularly used immunosuppressants vol.19, pp.5, 2018, https://doi.org/10.2217/pgs-2017-0182