Pharmacogenetics of methotrexate

Abstract

Methotrexate (MTX) has proven efficient in the treatment of a number of malignancies, as well as non-malignant disorders characterized by a rapid cellular growth. Yet some patients might develop resistance, while others could have toxic side effects. MTX achieves its cytotoxicity through the inhibition of folate-dependent enzymes, suggesting that the genes controlling their activity or the levels of folate cofactors can modulate drug efficacy and, thus, the sensitivity of a patient to MTX. Indeed, several studies, conducted mostly in leukemia and rheumatoid arthritis patients, have addressed the potential for tailoring MTX therapy based on a patient’s genetics. Several genetic variants have been shown to have a predictive role, among which the most frequently studied are those of methylenetetrahydrofolate reductase and thymidylate synthase genes. The other candidates, as well as gene–gene interactions, which may be even more important for the prediction of disease outcomes than the individual gene effects, are also briefly discussed.

Keywords::

• disease outcome
• folate cycle
• genetic variant
• leukemia
• methotrexate
• pharmacogenetics
• polymorphism
• rheumatoid arthritis
• therapeutic response
• variability