High-dose methotrexate in Egyptian pediatric acute lymphoblastic leukemia: the impact of ABCG2 C421A genetic polymorphism on plasma levels, what is next?

• Published in: Journal of cancer research and clinical oncology 2014-08, Vol.140 (8), p.1359-1365
• Main Authors: El Mesallamy, Hala O., Rashed, Wafaa M., Hamdy, Nadia M., Hamdy, Nayera
• Format: Article
• Language: English
• Subjects: Adolescent; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacokinetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; Cancer Research; Child; Child, Preschool; Children & youth; Egypt; Female; Genetic Association Studies; Genetics; Hematology; Humans; Infant; Internal Medicine; Leukemia; Male; Medicine; Medicine & Public Health; Methotrexate; Methotrexate - administration & dosage; Methotrexate - pharmacokinetics; Neoplasm Proteins - genetics; Oncology; Original Article – Clinical Oncology; Polymorphism; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Tissue Distribution - genetics
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-014-1670-y

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.