Methotrexate (MTX) is a wide-spectrum antimetabolite active against solid and hemato-logic malignancies. MTX penetrates the cells through the reduced folate carrier (RFC) and is activated by folylpoly-gamma-glutamate synthase (FPGS); in cancer cells resistant to MTX, defective polyglutamation due to the loss of FPGS activity (22), reduced expression of RFC (23), and increased levels of DHFR due to the C829C SNP in the 3'-untranslated region of the gene (24) have been described. In contrast, DHFR mutations occur rarely, and it seems unlikely that they play a major role in the acquired resistance to MTX (25). The 5,10-methylentetrahydrofolate reductase (MTHFR) enzyme is targeted by MTX; two of the best characterized variants in the genes are the C677T and A1298C SNPs. The common MTHFR C677T polymorphism decreases enzyme activity; in TT homozygous patients activity is decreased by 70% with respect to CC subjects, while TT subjects have significantly lower plasma folate concentrations than the CT and CC subjects (26). The TT genotype is associated with severe MTX-induced oral mucositis and delayed hematological recovery (27), suggesting that MTHFR genotyping could have a role in MTX dosing strategies in patients. Finally, screening of the RFC gene revealed at least seven SNPs, with one resulting in an amino acid substitution (Arg ! His) at position 27 of the carrier, although it was considered not to be relevant for folate and antifolate uptake (28). In contrast, a CATG frameshift causes the synthesis of a nonfunctional carrier, resulting in low MTX transport rates in cancer cells, and is a mechanism for drug resistance (28).

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