[Methotrexate resistance in acute leukemias]

Methotrexate is an important cytostatic drug in therapy of acute lymphoblastic leukemia. Cellular resistance to methotrexate might cause treatment failure. Possible mechanisms of resistance to methotrexate include: decreased accumulation and retention, decreased intracellular polyglutamylation, increased level or mutations of target enzymes, resistance to apoptosis. The literature review shows that resistance to methotrexate might be circumvented by continuous drug infusion in T-ALL, relapsed ALL and in AML. Another possibility to overcome mechanisms of resistance is the use of rationally designed new antifolates, which: can bypass RFC-mediated drug transport, are not dependent on polyglutamylation, have an improved affinity to target enzymes and target also other enzymes.