Abstract
The probability of event-free survival of childhood acute lymphoblastic leukemia (ALL) approaches 80% or more with the use of modern multiagent chemotherapeutic regimens. One major contribution to this success has been reduction of the rate of central nervous system (CNS) relapses to less than 5%. However, heterogeneity is observed with regard to the incidence of CNS relapse in homogenously treated patient populations. One potential explanation for this heterogeneity is variation in the genetic background of these populations. Glutathione S-transferase P1 and P-glycoprotein are implicated in resistance to a variety of chemotherapeutic agents and have been localized to the blood-brain barrier. In a matched case-control study, we investigated the associations between CNS relapse in childhood ALL and the presence of phenotypically relevant single nucleotide polymorphisms within the GSTP1 (codon 105 and 114) and MDR1 genes (ABCB1; coding for Pgp; exon 26, C3435T). Significant reductions in risk of CNS relapse were observed for patients homozygous for the GSTP1 Val105 allele as well as for patients with the MDR1 3435T/T or C/T genotype. For both genotypes, the effect was restricted to patients at intermediate or high risk of treatment failure.These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols.
Similar content being viewed by others
References
Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALLBFM study group from 1981 to 1995. Leukemia. 2000;14:2205–2222.
Gaynon PS, Trigg ME, Heerema NA, et al. Children’s Cancer Group trials in childhood acute lymphoblastic leukemia: 1983- 1995. Leukemia. 2000;14:2223–2233.
Pui CH, Boyett JM, Rivera GK, et al. Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St. Jude Children’s Research Hospital. Leukemia. 2000;14:2286–2294.
Pinkel D, Woo S. Prevention and treatment of meningeal leukemia in children. Blood. 1994;84:355–366.
Eaton DL, Bammler TK. Glutathione S-transferases. In: Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M, eds. Metabolic Drug Interactions. Philadelphia: Lippincott Williams & Wilkins; 2000:175–189.
Bellamy WT. P-glycoproteins and multidrug resistance. Annu Rev Pharmacol Toxicol. 1996;36:161–183.
Board PG, Webb GC, Coggan M. Isolation of a cDNA clone and localization of the human glutathione S-transferase 3 gene to chromosome bands 11q13 and 12q13-14. Ann Hum Genet. 1989;53:205–213.
Board P, Coggan M, Johnston P, Ross V, Suzuki T, Webb G. Genetic heterogeneity of the human glutathione transferases: a complex of gene families. Pharmacol Ther. 1990;48:357–369.
Hu X, Xia H, Srivastava SK, et al. Activity of four allelic forms of glutathione S-transferase hGSTP1-1 for diol epoxides of polycyclic aromatic hydrocarbons. Biochem Biophys Res Commun. 1997;238:397–402.
Zimniak P, Nanduri B, Pikula S, et al. Naturally occurring human glutathione S-transferase GSTP-1 isoforms with isoleucin and valine in position 104 differ in enzymic properties. Eur J Biochem. 1994;224:893–899.
Hoffmeyer S, Burk O, von Richter O, et al. 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 U S A. 2000;97:3473–3478.
Siegsmund M, Brinkmann U, Schaffeler E, et al. Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol. 2002;13:1847–1854.
Hitzl M, Drescher S, van der Kuip H, et al. 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. 2001;11:293–298.
Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human mdr1 drug transporter. Annu Rev Pharmacol Toxicol. 2003;43:285–307.
Carder PJ, Hume R, Fryer AA, Strange RC, Lauder J, Bell JE. Glutathione S-transferase in human brain. Neuropathol Appl Neurobiol. 1990;16:293–303.
Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97:2517–2524.
Sun H, Dai H, Shaik N, Elmquist WF. Drug efflux transporters in the CNS. Adv Drug Deliv Rev. 2003;55:83–105.
Anderer G, Schrappe M, Brechlin AM, et al. Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia. Pharmacogenetics. 2000;10:715–726.
Reiter A, Schrappe M, Ludwig W-D, et al. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994;84:3122–3133.
Schrappe M, Reiter A, Ludwig W-D, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood. 2000;95:3310–3322.
Harries LW, Stubbins MJ, Forman D, Howard GC, Wolf CR. Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis. 1997;18:641–644.
Harris MJ, Coggan M, Langton L, Wilson SR, Board PG. Polymorphism of the Pi class glutathione S-transferase in normal populations and cancer patients. Pharmacogenetics. 1998;8:27–31.
Hennekens CH, Buring JE. Epidemiology in Medicine. Boston: Little, Brown; 1987:295–304.
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58.
Llorente L, Richaud-Patin Y, Diaz-Borjon A, et al. Multidrug resistance-1 (MDR-1) in rheumatic autoimmune disorders, I: increased P-glycoprotein activity in lymphocytes from rheumatoid arthritis patients might influence disease outcome. Joint Bone Spine. 2000;67:30–39.
Farrell RJ, Murphy A, Long A, et al. High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy. Gastroenterology. 2000;118:279–288.
Siddiqui A, Kerb R, Weale ME, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003;348:1442–1448.
Jamroziak K, Mlynarski W, Balcerczak E, et al. Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol. 2004;72:314–321.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Stanulla, M., Schäffeler, E., Arens, S. et al. GSTP1 and MDR1 Genotypes and Central Nervous System Relapse in Childhood Acute Lymphoblastic Leukemia. Int J Hematol 81, 39–44 (2005). https://doi.org/10.1532/IJH97.E0418
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1532/IJH97.E0418