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Cancer Chemotherapy and Pharmacology
Erschienen in: Cancer Chemotherapy and Pharmacology 2/2014

01.08.2014 | Original Article

Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia

verfasst von: Shu-mei Wang, Lu-lu Sun, Wei-xin Zeng, Wan-shui Wu, Guo-liang Zhang

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2014

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Abstract

Purpose

To investigate the correlation between common genetic polymorphisms of folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), and methylenetetrahydrofolate reductase (MTHFR) and serum levels of methotrexate (MTX) in Chinese children with acute lymphoblastic leukemia (ALL).

Methods

Ninety-one children with ALL who received high-dose MTX were recruited. The polymorphisms FPGS (rs1544105 G>A), GGH (rs3758149 C>T), and MTHFR (rs1801133 C>T) were genotyped through polymerase chain reaction-restriction fragment length polymorphism analysis. Serum MTX was measured by fluorescence polarization immunoassay. The association between targeted polymorphisms and MTX concentration-to-dose (C/D) ratios was assessed, and between targeted polymorphisms and the percent of MTX above the therapeutic threshold (40 µmol/L).

Results

The minor allele frequencies of rs1544105 G (34.1 %), rs3758149 T (19.2 %), and rs1801133 C (48.4 %) observed in our population were significantly lower than those reported for European populations (64.2, 30.8, and 69.0 %, respectively). The association between the GGH rs3758149 polymorphism and MTX C/D was gender-specific; in girls, the MTX C/D at 24 h of GGH rs3758149 CC carriers (12.09 μmol/L per g/m2) was significantly lower than that of CT or TT carriers (16.80 μmol/L per g/m2). The percent of serum MTX above the therapeutic threshold in GGH rs3758149 CC carriers (18.3 %) was significantly lower than that of CT and TT carriers (38.7 %). The MTX C/D ratios at 24 h and the percent of MTX >40 µmol/L for the A-T-T (three variant alleles) haplotype were significantly higher than those for other haplotypes combined (P < 0.05).

Conclusions

These data indicate that FPGS rs1544105, GGH rs3758149, and MTHFR rs1801133 polymorphisms contribute to the variability of MTX pharmacokinetics, and their genotyping may be useful to reduce toxicities associated with MTX therapy.
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Metadaten
Titel
Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia
verfasst von
Shu-mei Wang
Lu-lu Sun
Wei-xin Zeng
Wan-shui Wu
Guo-liang Zhang
Publikationsdatum
01.08.2014
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 2/2014
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-014-2507-8

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