Molecular mechanisms of methotrexate resistance

Methotrexate (MTX) is a purine analog antimetabolite that is widely used in the treatment of neoplastic disease, rheumatoid arthritis, and severe psoriasis. Uptake of MTX into cells is dependent upon the reduced folate carriers (RFCs), while the cellular level of MTX is maintained by its polyglutamylation. The development of MTX resistance, which reduces MTX efficacy in a variety of disease treatments, has been discussed in many studies. Resistance factors include defective or slow uptake of MTX with RFCs or increased efflux via ATP-binding cassette (ABC) multidrug transporters, certain alterations in targeted enzymes, genetic polymorphisms, impaired MTX polyglutamylation, increased salvage and increased metabolism of MTX. However, the pharmacokinetic and cellular resistance mechanisms of MTX are still not completely understood. This chapter discusses current knowledge of the molecular basis of MTX resistance based on data obtained from both pre-clinical and clinical studies. In addition, emerging mechanisms for MTX treatment are also discussed. An in-depth understanding of the molecular mechanisms behind the MTX resistance could help facilitate the optimal use of antifolate therapy as well as new drug development.