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High Expression of Lung Resistance Protein mRNA at Diagnosis Predicts Poor Early Response to Induction Chemotherapy in Childhood Acute Lymphoblastic Leukemia

  • Bhatia, Prateek (Department of Paediatrics, Advanced Pediatric Centre) ;
  • Masih, Shet (MDRL Laboratories) ;
  • Varma, Neelam (Department of Hematology, Post Graduate Institute of Medical Education and Research (PGIMER)) ;
  • Bansal, Deepak (Pediatric Hemato-oncology Unit, Department of Paediatrics, Post Graduate Institute of Medical Education and Research (PGIMER)) ;
  • Trehan, Amita (Pediatric Hemato-oncology Unit, Department of Paediatrics, Post Graduate Institute of Medical Education and Research (PGIMER))
  • Published : 2015.10.06

Abstract

Background: Treatment failure in leukemia is due to either pharmacokinetic resistance or cell resistance to drugs. Materials and Methods: Gene expression of multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP) and low resistance protein (LRP) was assessed in 45 pediatric ALL cases and 7 healthy controls by real time PCR. The expression was scored as negative, weak, moderate and strong. Results: The male female ratio of cases was 2.75:1 and the mean age was 5.2 years. Some 26/45 (58%) were in standard risk, 17/45(38%) intermediate and 2/45 (4%) in high risk categorie, 42/45 (93%) being B-ALL and recurrent translocations being noted in 5/45 (11.0%). Rapid early response (RER) at day 14 was seen in 37/45 (82.3%) and slow early response (SER) in 8/45 (17.7%) cases. Positive expression of MDR-1, LRP and MRP was noted in 14/45 (31%), 15/45 (33%) and 27/45 (60%) cases and strong expression in 3/14 (21%), 11/27 (40.7%) and 8/15 (53.3%) cases respectively. Dual or more gene positivity was noted in 17/45 (38%) cases. 46.5 % (7/15) of LRP positive cases at day 14 were in RER as compared to 100% (30/30) of LRP negative cases (p<0.05). All 8 (100%) LRP positive cases in SER had strong LRP expression (p=<0.05). Moreover, only 53.3% of LRP positive cases were in haematological remission at day 30 as compared to 100% of LRP negative cases (p=<0.05). Conclusions: Our study indicated that increased LRP expression at diagnosis in pediatric ALL predicts poor response to early treatment and hence can be used as a prognostic marker. However, larger prospective studies with longer follow up are needed, to understand the clinical relevance of drug resistance proteins.

Keywords

ALL;chemotherapy;drug resistance proteins;pediatric;response

References

  1. Bhadri VA, Trahair TN, Lock RB (2012). Glucocorticoid resistance in paediatric acute lymphoblastic leukaemia. J Paediatr Child Health, 48, 634-40. https://doi.org/10.1111/j.1440-1754.2011.02212.x
  2. El-Sharnouby JA, Abou El-Enein AM, El Ghannam DM, et al (2010). Expression of lung resistance protein and multidrug resistance-related protein (MRP1) in pediatric acute lymphoblastic leukemia. J Oncol Pharm Pract, 16, 179-88. https://doi.org/10.1177/1078155209351329
  3. ET Valera, CA Scrideli, RG de P Querioz, et al (2004). Multiple drug resistance protein (MDR-1), multidrug resistance related protein (MRP) and lung resistance protein (LRP) gene expression in childhood acute lymphoblastic leukemia. Sao Paulo Med J, 122, 166-71. https://doi.org/10.1590/S1516-31802004000400007
  4. F Mahjoubi, S Akbari (2012). Multidrug resistance associated protein 1 predicts relapse in Iranian childhood acute lymphoblastic leukemia. Asian Pac J Cancer Prev, 13, 2285-9. https://doi.org/10.7314/APJCP.2012.13.5.2285
  5. Fedasenka UU, Shman TV, Savitski VP, Belevcev MV (2008). Expression of MDR-1, LRP, BCRP and Bcl-2 genes at diagnosis of childhood ALL: comparison with MRD status after induction therapy. Exp Oncol, 30, 248-52.
  6. Gaynon PS, Steinherz PG, Bleyer WA, et al (1993). Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Children's Cancer Group Study CCG-106. J Clin Oncol, 11, 2234-42.
  7. HJ Huh, CJ Park, S Jang, et al (2006). Prognostic significance of multidrug resistance gene (MDR1), multidrug related protein (MRP) and lung resistance protein (LRP) mRNA expression in acute leukemia. J Korean Med Sci, 21, 253-8. https://doi.org/10.3346/jkms.2006.21.2.253
  8. Kaatsch P (2010). Epidemiology of childhood cancer. Cancer Treat Rev, 36, 277-85. https://doi.org/10.1016/j.ctrv.2010.02.003
  9. Kakihara T, Tanaka A, Watanabe A, et al (1999). Expression of multidrug resistance related genes does not contribute to risk factors in newly diagnosed childhood acute lymphoblastic leukemia. Pediatr Int, 416, 641-7.
  10. Kourti M, Vavatsi N, Gombakis N, et al (2007). Expression of multidrug resistance 1 (MDR1), multidrug resistance-related protein (MRP1) and lung resistance protein (LRP) and breast cancer protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia. Int J Hematol, 86, 166-73. https://doi.org/10.1532/IJH97.E0624
  11. Lo Nigro L (2013). Biology of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol, 35, 245-52.
  12. Madara K, Dmitrijs R, Linda P, et al (2014). Lack of Association between Polymorphisms in Genes MTHFR and MDR1 with Risk of Childhood Acute Lymphoblastic Leukemia. Asian Pac J Cancer Prev, 16, 9707-11.
  13. ML den Boer, R Pieters, KM Kazemier, et al (1998). Relationship between major vault protein/lung resistance protein, multidrug resistance related protein, P-glycoprotein expression and drug resistance in childhood leukemia. Blood, 91, 2092-8.
  14. ML Den Boer, Pieters R, Kazemier KM, et al (1998). The modulation effect of PSC 833, cyclosporine A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia. Leukemia, 12, 912-20. https://doi.org/10.1038/sj.leu.2401035
  15. Naureen M, Zehra F, Ahmed N (2013). Childhood acute lymphoblastic leukaemia: experience from a single tertiary care facility of Pakistan. J Pak Med Assoc, 63, 1399-404.
  16. Norgaard JM, Hokland P (2000). Biology of multiple drug resistance in acute leukemia. Int J Hematol, 72, 290-7.
  17. Ogretmen B, Barredo JC, Safa AR (2000). Increased expression of lung resistance-related protein and multidrug resistanceassociated protein messenger RNA in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol, 22, 45-9. https://doi.org/10.1097/00043426-200001000-00009
  18. Panya S, Surapon W, Gavivann V, et al (2015). Outcome of Childhood Acute Lymphoblastic Leukemia Treated Using the Thai National Protocols. Asian Pac J Cancer Prev, 16, 4609-14. https://doi.org/10.7314/APJCP.2015.16.11.4609
  19. Pieters R, Klumper E, Kaspers GJ, et al (1997). Everything you always wanted to know about cellular drug resistance in childhood acute lymphoblastic leukemia. Crit Rev Oncol Hematol, 25, 11-26. https://doi.org/10.1016/S1040-8428(96)00223-5
  20. Pui CH, Mullighan CG, Evans WE, Relling MV (2012). Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood, 120, 1165-74. https://doi.org/10.1182/blood-2012-05-378943
  21. Rivera GK, Raimondi SC, Williams DL, et al (1991). Improved outcome in childhood acute lymphoblastic leukemia with reinforced early treatment and rotational combination chemotherapy. Lancet, 337, 61-6. https://doi.org/10.1016/0140-6736(91)90733-6
  22. Sauerbrey A, Voigt A, Wittig S, et al (2002). Messenger RNA analysis of the multidrug resistance related protein (MRP1) and the lung resistance protein (LRP) in de novo and relapsed childhood acute lymphoblastic leukemia. Leuk Lymphoma, 43, 875-9. https://doi.org/10.1080/10428190290017024
  23. Volm M, Stammler G, Zintl F, et al (1997). Expression of lung resistance related protein (LRP) in initial and relapsed childhood acute lymphoblastic leukemia. Anticancer Drugs, 8, 662-5. https://doi.org/10.1097/00001813-199708000-00003
  24. Wanida P, Samart P, Panee C, et al (2015). MDR1 C3435T and C1236T Polymorphisms: Association with High-risk Childhood Acute Lymphoblastic Leukemia. Asian Pac J Cancer Prev, 16, 2839-43. https://doi.org/10.7314/APJCP.2015.16.7.2839
  25. Zhang JB, Sun Y, Dong J, et al (2005). Expression of lung resistance protein and multidrug resistance related protein in naive childhood acute leukemia and their clinical significance. Al Zheng, 24, 1015-7.

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