RGD Reference Report - Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia. - Rat Genome Database

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Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia.

Authors: El-Khodary, NM  El-Haggar, SM  Eid, MA  Ebeid, EN 
Citation: El-Khodary NM, etal., Med Oncol. 2012 Sep;29(3):2053-62. doi: 10.1007/s12032-011-9997-6. Epub 2011 Jun 5.
RGD ID: 10449407
Pubmed: PMID:21644011   (View Abstract at PubMed)
DOI: DOI:10.1007/s12032-011-9997-6   (Journal Full-text)

Methotrexate inhibits the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by methylenetetrahydrofolate reductase (MTHFR). MTHFR has a common functional polymorphism C677T. The present study aimed to investigate the prevalence of MTHFR polymorphisms in Egyptian children with ALL and the relation to MTX-related toxicity, relapse, and MTX pharmacokinetic parameters. Forty patients with ALL were included in the study. They were treated according to ALL-NCI total XIII protocol. MTX-related toxicity and MTX pharmacokinetic parameters were assessed during therapy. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay, and MTX pharmacokinetic parameters were assessed by HPLC. The MTHFR C677T polymeric allele frequencies were 55, 35, and 10% for CC, CT, and TT genotypes, respectively, among the studied patients with ALL. MTX therapy was significantly associated with toxicity signs in TT genotype: elevated transaminases (P < 0.0001), elevated serum alpha 1-microglobulin protein (P < 0.0001), anemia (P < 0.0001), neutropenia (P < 0.0001), thrombocytopenia (P < 0.0001), and elevated CSF-beta-glucuronidase activity (P < 0.0001). Patients with TT genotype showed significant increase in MTX t((1/2)) and AUC (P < 0.0001), while MTX elimination rate and total body clearance were significantly decreased (P < 0.0001 and P < 0.05, respectively) compared with CC genotype. The TT genotype was significantly associated with relapse in 2 years in 50% compared with 28.57% in CT and 13.64% in CC alleles. The overall 2-year survival was significantly lower in TT genotype (50%) compared with CC genotype (90.91%; P = 0.01). MTHFR TT genotype is significantly associated with increased toxicity during methotrexate therapy as well as increased relapse rate in pediatric patients with ALL. In future, MTX dose adjustment in ALL treatment protocols should be considered based on patient's genotype.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
acute lymphoblastic leukemia treatmentIAGP 10449407DNA:missense mutation:cds:677C>T (human)RGD 
acute lymphoblastic leukemia treatmentISOMTHFR (Homo sapiens)10449407; 10449407DNA:missense mutation:cds:677C>T (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Anemia treatmentIAGP 10449407DNA:missense mutation:cds:677C>TRGD 
Increased alpha-globulin treatmentIAGP 10449407DNA:missense mutation:cds:677C>TRGD 
Neutropenia treatmentIAGP 10449407DNA:missense mutation:cds:677C>TRGD 
Thrombocytopenia treatmentIAGP 10449407DNA:missense mutation:cds:677C>TRGD 
Objects Annotated

Genes (Rattus norvegicus)
Mthfr  (methylenetetrahydrofolate reductase)

Genes (Mus musculus)
Mthfr  (methylenetetrahydrofolate reductase)

Genes (Homo sapiens)
MTHFR  (methylenetetrahydrofolate reductase)


Additional Information