DOI QR코드

DOI QR Code

Is the MDR1 C3435T Polymorphism Responsible for Oral Mucositis in Children with Acute Lymphoblastic Leukemia?

  • Bektas-Kayhan, Kivanc (Department of Oral Surgery and Medicine, Faculty of Dentistry, Istanbul University) ;
  • Kucukhuseyin, Ozlem (Department of Molecular Medicine, Institute of Experimental Medicine, Istanbul University) ;
  • Karagoz, Gizem (Department of Oral Surgery and Medicine, Faculty of Dentistry, Istanbul University) ;
  • Unur, Meral (Department of Oral Surgery and Medicine, Faculty of Dentistry, Istanbul University) ;
  • Ozturk, Oguz (Department of Molecular Medicine, Institute of Experimental Medicine, Istanbul University) ;
  • Unuvar, Aysegul (Department of Pediatric Hematology and Oncology, Faculty of Medicine, Istanbul University) ;
  • Devecioglu, Omer (Department of Pediatric Hematology and Oncology, Faculty of Medicine, Istanbul University) ;
  • Yilmaz-Aydogan, Hulya (Department of Molecular Medicine, Institute of Experimental Medicine, Istanbul University)
  • Published : 2012.10.31

Abstract

Background and Aim: Although the functional consequences of MDR-1 polymorphisms have been the subject of numerous studies, to the best to our knowledge, associations with clinical side effects of anticancer drugs have yet to be assessed. Our aim was to clarify any role of the C3435T polymorphism of the MDR1 gene in oral mucositis and its relation with elevated reactive oxygen species (ROS) levels, in children with acute lymphoblastic leukemia (ALL). Materials and Methods: The distribution of the MDR-1 C3435T polymorphism in 47 patients with ALL was determined by RFLP and compared with that of 68 healthy controls. Results: There were no association in distribution of genotypes of MDR-1 C3435T polymorphism and the risk of ALL. Oral mucositis were detected in 78.7% (n=37) of the patients and significantly related to the MDR-1 CT genotype (p=0.042), as confirmed by logistic regression analysis. Conclusion: Our preliminary data suggest that children carrying the CT genotype are more prone to develop oral mucositis, which might mean that the heterozygous genotype leads to accumulation of more reactive oxygen species. Since a limited number of patients was investigated, further studies are needed to confirm these findings.

Keywords

References

  1. Aladjidi N, Auvrignon A, Leblanc T, et al (2003). Outcome in children with relapsed acute myeloid leukemia after initial treatment with the French Leucemie Aique Myeloide Enfant (LAME) 89/91 protocol of the French Society of pediatric hematology and immunology. J Clin Oncol, 21, 4377-85. https://doi.org/10.1200/JCO.2003.11.066
  2. Bradley G, Juranka PF, Ling V (1988). Mechanisms of multidrug resistance. Biochim Biophys Acta, 948, 87-128.
  3. Cascorbi I, Gerloff T, Johne A, et al (2001). Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in White subjects. Clin Pharmacol Ther, 69, 169-74. https://doi.org/10.1067/mcp.2001.114164
  4. Cascorbi I, Gerloff T, Johne A, et al (2001). Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in White subjects. Clin Pharmacol Ther, 69, 169-74. https://doi.org/10.1067/mcp.2001.114164
  5. Chong AS, Markham PN, Gebel HM, Bines SD, Coon JS (1995). Diversemultidrugresistance-modification agents inhibit cytolytic activity of natural killer cells. Cancer Immunol Immunother, 36, 133-9.
  6. Drach J, Gsur A, Hamilton G, et al (1996). Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-g in normal human T lymphocytes. Blood, 88, 1747-54.
  7. Drach J, Gsur A, Hamilton G, et al (1996). Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-g in normal human T lymphocytes. Blood, 88, 1747-54.
  8. Goldstein LJ, Galski H, Fojo A, et al (1989). Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst, 81, 116-24. https://doi.org/10.1093/jnci/81.2.116
  9. Greaves M (2006). Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer, 6, 193-203. https://doi.org/10.1038/nrc1816
  10. Gupta S, KimCH, Tsuruo T, Gollapudi S (1992). Preferential expression and activity of multidrug resistance gene 1 product (P-glycoprotein), a functionally active efflux pump, in human CD8+ T cells: a role in cytotoxic effector function. J Clin Immunol, 12, 451-8. https://doi.org/10.1007/BF00918857
  11. Hitzl M, Drescher S, Van der Kuip H, et al (2001). The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics, 11, 293-8. https://doi.org/10.1097/00008571-200106000-00003
  12. Hoffmeyer S, Burk O, Von Richter O, et al (2000). Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA, 97, 3473-8. https://doi.org/10.1073/pnas.97.7.3473
  13. Illmer T, Schuler US, Thiede C, et al (2002). MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res, 62, 4955-62.
  14. Jamroziak K, Mlynarski W, Balcerczak E, et al (2004). Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol, 72, 314-21. https://doi.org/10.1111/j.1600-0609.2004.00228.x
  15. Kim RB, Leake BF, Choo EF, et al (2001). Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther, 70, 189-99. https://doi.org/10.1067/mcp.2001.117412
  16. Kroetz DL, Pauli-Magnus C, Hodges LM, et al (2003). Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics, 13, 481-94. https://doi.org/10.1097/00008571-200308000-00006
  17. Lin JH, Yamazaki M (2003). Role of p-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet, 42, 59-98. https://doi.org/10.2165/00003088-200342010-00003
  18. Liscovitch M, Lavie Y (2002). Cancer multidrug resistance: a review of recent drug discovery research. IDrugs, 5, 349-55.
  19. Miladpour B, Shokouhi AM, Shirdel A, et al (2009). Association of acute lymphoblastic leukemia and MDR1 gene polymorphism in an ethnic Iranian population. IJBC, 2, 63-7.
  20. Miller SA, Dykes DD, Polesky HF (1998). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 16, 1215.
  21. Nakamura T, Sakaeda T, Horinouchi M, et al (2002). Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther, 71, 297-303. https://doi.org/10.1067/mcp.2002.122055
  22. Pawlik A, Baskiewicz-Masiuk M, Machalinski B, Kurzawski M, Gawronska-Szklarz B (2005). Involvement of C3435T and G2677T multidrug resistance gene polymorphisms in release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. Eur J Pharmacol, 528, 27-36. https://doi.org/10.1016/j.ejphar.2005.10.068
  23. Pinto LP, Souza LB, Gordon-Nunez MA, et al (2006). Prevention of oral lesions in children with acute lymphoblastic leukemia. Int J Pediatric Otorhinolaryngol, 70, 1847-51. https://doi.org/10.1016/j.ijporl.2006.04.016
  24. Pui CH, Schrappe M, Ribeiro R, Niemeyer CM (2004). Childhood and adolescent lymphoid and myeloid leukemia. Hematology Am Soc Hematol Educ Program, 1, 118-45.
  25. Rao DN, Anuradha C, Vishnupriya S, et al (2010). Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev, 11, 1063-66.
  26. Sakaeda T, Nakamura T, Okumura K (2002). MDR1 genotyperelated pharmacokinetics and pharmacodynamics. Biol Pharm Bull, 25, 1391-400. https://doi.org/10.1248/bpb.25.1391
  27. Sandler DP, Ross JA (1997). Epidemiology of acute leukemia in children and adults. Semin Oncol, 24, 3-16.
  28. Schinkel AH (1997). The physiological function of drugtransporting P-glycoproteins. Semin Cancer Biol, 8, 161-70. https://doi.org/10.1006/scbi.1997.0068
  29. Schinkel AH (1997). The physiological function of drugtransporting P-glycoproteins. Semin Cancer Biol, 8, 161-70. https://doi.org/10.1006/scbi.1997.0068
  30. Siegsmung M, Brinkmann U, Scheffeler E, et al (2002). Association of the P-glycoprotein transporter MDR1 (C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol, 13, 1847-54. https://doi.org/10.1097/01.ASN.0000019412.87412.BC
  31. Sills GJ, Mohanraj R, Butler E, et al (2005). Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment. Epilepsia 46, 643-47. https://doi.org/10.1111/j.1528-1167.2005.46304.x
  32. Sonis ST (2011). Oral mucositis. Anticancer Drugs, 22, 607-12. https://doi.org/10.1097/CAD.0b013e3283462086
  33. Tanabe M, Ieiri I, Nagata N, et al (2001). Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther, 297, 1137-43.
  34. Tanabe M, Ieiri I, Nagata N, et al (2001). Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther, 297, 1137-43.
  35. Vijayakrishnan J, Houlston RS (2010). Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica, 95, 1405-14. https://doi.org/10.3324/haematol.2010.022095
  36. Wang J, Wang B, Bi J, Li K, Di J (2012). MDR1 gene C3435T polymorphism and cancer risk: a meta-analysis of 39 casecontrol studies. J Cancer Res Clin Oncol, 138, 979-89. https://doi.org/10.1007/s00432-012-1171-9
  37. Wartenberg M, Hoffmann E, Schwindt H, et al (2005). Reactive oxygen species-linked regulation of the multidrug resistance transporter P-glycoprotein in Nox-1 overexpressing prostate tumor spheroids. FEBS Lett, 579, 4541-9. https://doi.org/10.1016/j.febslet.2005.06.078

Cited by

  1. The role of MDR1 (C3435T) gene polymorphism in Egyptian acute lymphoblastic leukemia vol.24, pp.1, 2015, https://doi.org/10.1007/s00580-013-1859-5
  2. Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: An informative gene network analysis vol.12, pp.7, 2017, https://doi.org/10.1371/journal.pone.0180396
  3. Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies vol.15, pp.11, 2014, https://doi.org/10.2217/pgs.14.97
  4. Gene Polymorphisms and Their Associations with Clinical Outcomes vol.20, pp.10, 2016, https://doi.org/10.1089/gtmb.2015.0287
  5. Predicting mucositis risk associated with cytotoxic cancer treatment regimens pp.1751-4258, 2018, https://doi.org/10.1097/SPC.0000000000000339