PURPOSE: High-dose methotrexate (HD-MTX) is a cornerstone antineoplastic drug in most treatment protocols of pediatric acute lymphoblastic leukemia (ALL). Among the membrane efflux transporters of MTX, the human breast cancer resistant protein is the second member of the G subfamily of ATP-binding cassette (ABC) efflux pump (ABCG2). A single-nucleotide polymorphism (SNP) in ABCG2, the exchange of C to A at position 421, represents 13 % in the Middle Eastern population. We studied the effect of this SNP on the plasma levels of HD-MTX in Egyptian pediatric ALL. METHODS: Two hundred ALL patients were recruited from Children's Cancer Hospital Egypt-57357, and all were treated according to the St Jude Total XV protocol. Determination of plasma MTX levels was done at 23, 42 and 68 h. Genotyping of C421A of ABCG2 was done by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We found 14.5 % of the variant allele of the ABCG2 C421A SNP. The statistical association between ABCG2 421C>A SNP and the cutoff toxic plasma level of 24 h HD-MTX infusion at different time points tested was not statistically significant. There was no statistical significance between steady-state plasma concentration in patients with and without with this SNP. CONCLUSION: To date, this is the largest study on Egyptian ALL patients for this SNP. This study shows that there is no effect of ABCG2 421C>A on plasma concentrations of HD-MTX. Replacing candidate gene association studies with genome-wide studies of HD-MTX is now mandatory and is part of our research blueprint.
PURPOSE: High-dose methotrexate (HD-MTX) is a cornerstone antineoplastic drug in most treatment protocols of pediatric acute lymphoblastic leukemia (ALL). Among the membrane efflux transporters of MTX, the humanbreast cancer resistant protein is the second member of the G subfamily of ATP-binding cassette (ABC) efflux pump (ABCG2). A single-nucleotide polymorphism (SNP) in ABCG2, the exchange of C to A at position 421, represents 13 % in the Middle Eastern population. We studied the effect of this SNP on the plasma levels of HD-MTX in Egyptian pediatric ALL. METHODS: Two hundred ALL patients were recruited from Children's Cancer Hospital Egypt-57357, and all were treated according to the St Jude Total XV protocol. Determination of plasma MTX levels was done at 23, 42 and 68 h. Genotyping of C421A of ABCG2 was done by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We found 14.5 % of the variant allele of the ABCG2C421A SNP. The statistical association between ABCG2 421C>A SNP and the cutoff toxic plasma level of 24 h HD-MTX infusion at different time points tested was not statistically significant. There was no statistical significance between steady-state plasma concentration in patients with and without with this SNP. CONCLUSION: To date, this is the largest study on Egyptian ALL patients for this SNP. This study shows that there is no effect of ABCG2 421C>A on plasma concentrations of HD-MTX. Replacing candidate gene association studies with genome-wide studies of HD-MTX is now mandatory and is part of our research blueprint.
Authors: M Maliepaard; G L Scheffer; I F Faneyte; M A van Gastelen; A C Pijnenborg; A H Schinkel; M J van De Vijver; R J Scheper; J H Schellens Journal: Cancer Res Date: 2001-04-15 Impact factor: 12.701
Authors: Torben S Mikkelsen; Alex Sparreboom; Cheng Cheng; Yinmei Zhou; James M Boyett; Susana C Raimondi; John C Panetta; W Paul Bowman; John T Sandlund; Ching-Hon Pui; Mary V Relling; William E Evans Journal: J Clin Oncol Date: 2011-03-28 Impact factor: 44.544
Authors: N Simon; A Marsot; E Villard; S Choquet; H-X Khe; N Zahr; P Lechat; V Leblond; J-S Hulot Journal: Pharmacogenomics J Date: 2012-10-16 Impact factor: 3.550
Authors: Owen M Woodward; Anna Köttgen; Josef Coresh; Eric Boerwinkle; William B Guggino; Michael Köttgen Journal: Proc Natl Acad Sci U S A Date: 2009-06-08 Impact factor: 11.205