Effects of SCT genetic polymorphisms on methotrexate concentrations and toxicities in Chinese children with acute...

Area of Science:

• Pharmacogenomics
• Oncology
• Molecular Biology

Background:

• Solute carrier (SLC) transporters are vital for anticancer drug uptake, including methotrexate (MTX).
• Genetic variations in SLC transporters can influence drug efficacy and toxicity.
• Acute lymphoblastic leukemia (ALL) treatment often involves MTX, necessitating understanding of factors affecting its pharmacokinetics.

Purpose of the Study:

• To investigate the association between nonsynonymous single nucleotide polymorphisms (SNPs) in *SLC19A1*, *SLCO1B1*, and *SLCO1B3* and MTX exposure, toxicity, and prognosis in ALL patients.
• To identify specific SNPs that correlate with MTX pharmacokinetics and clinical outcomes.
• To explore the potential of SNP analysis for personalizing MTX therapy in pediatric ALL.

Main Methods:

• Genotyping of nonsynonymous SNPs in *SLC19A1*, *SLCO1B1*, and *SLCO1B3* in 148 ALL patients.
• Measurement of serum MTX concentrations at 24 hours post-administration.
• Statistical analysis to correlate SNP genotypes with MTX levels, toxicities (hematological and hepatic), and prognosis.

Main Results:

• The *SLCO1B3* rs7311358 polymorphism was linked to median dose-normalized MTX concentrations at 24 hours.
• Significant differences in high serum MTX levels (>40 µmol/L) at 24 hours were observed among carriers of different *SLC19A1* rs1051266 genotypes.
• The *SLC19A1* rs1051266 G>A polymorphism showed significant associations with both hematological and hepatic toxicities.

Conclusions:

• Nonsynonymous SNPs in *SLC19A1* and *SLCO1B3* influence MTX pharmacokinetics and toxicity in ALL patients.
• Genetic analysis of solute carrier transporters (SCTs) can provide insights into interpatient variability in MTX exposure.
• SNP profiling may aid in tailoring MTX treatment strategies to improve outcomes and reduce toxicity in pediatric ALL.