Association of ABCB1, ABCC5 and xanthine oxidase genetic polymorphisms with methotrexate adverse reactions in Mexican pediatric patients with ALL.
BACKGROUND
Acute lymphoblastic leukemia (ALL) is one of the most frequent oncological disorders in pediatric populations. To date, the drug of choice for the treatment of ALL is methotrexate, a drug associated with a high risk of adverse reactions (ADRs). The xanthine oxidase (XO) polymorphisms, 1936A>G and 2107A>G, as well as the polymorphic variants derived from ATP-binding cassette transporter gene subfamilies, ABCB1 and ABCC5, of drug resistant codifying genes, are implicated as precursors of drug-related neurologic, hepatic, and renal toxicities. Our aim was to determine whether the mentioned polymorphisms are risk or protective factors for the development of adverse reactions by methotrexate in our pediatric population with ALL.


METHODS
A total of 35 Mexican children from Centro Estatal de Cancerología-Durango, Mexico, with ALL and the previously noted polymorphisms as determined qPCR were studied. At the same time, a 12-month drug monitoring program was conducted in accordance with WHO-PAHO guidelines for pharmacovigilance.


RESULTS
The ABCB11936A>G and 2107A>G and ABCC5 3414+434A>C polymorphisms were not associated with methotrexate ADRs. Single nucleotide polymorphisms (SNPs) of ABCB1 1236C>T (OR 0.19, 95% CI: 0.03-0.9, p<0.05) and ABCC5 3933+313T>C (OR 0.12, 95% CI: 0.027-0.58, p<0.05) were associated with methotrexate ADRs.


CONCLUSIONS
SNPs 1236C>T of ABCB1 and ABCC5 3933+313T>C are not associated with the development of typical ADRs by methotrexate, rather, they showed a protective factor for myelosuppression in the studied sick population.
Fausto
http://orcid.org/0000-0003-1229-8257
F
Zaruma-Torres
Ismael
I
Lares-Asseff
Aarón
A
Reyes-Espinoza
Verónica
V
Loera-Castañeda
Isaías
I
Chairez-Hernández
Martha
M
Sosa-Macías
Carlos
C
Galaviz-Hernández
Horacio
H
Almanza-Reyes
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002173:Cancer Care Facilities; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D060046:Maintenance Chemotherapy / Q000009:adverse effects; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008800:Mexico; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D038042:Myelopoiesis / Q000187:drug effects; D060735:Pharmacovigilance; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D011446:Prospective Studies; D014969:Xanthine Oxidase / Q000235:genetics* / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014969:Xanthine Oxidase; C513055:ABCB1 protein, human; C120809:ABCC5 protein, human