Sensitivity and resistance to methotrexate in childhood B-progenitor cell acute lymphoblastic leukemia

Both clinical and pharmacokinetic studies have indicated that methotrexate may be a key drug in the treatment and cure of children with acute lymphoblastic leukemia. This conclusion has been strengthened by studies of methotrexate polyglutamate formation in lymphoblasts obtained at diagnosis from affected children. The extent of accumulation of methotrexate polyglutamates appears to correlate with likelihood of cure. Sensitivity to methotrexate, reflected in high levels of lymphoblast methotrexate polyglutamates, is likely to be the explanation for the curability of hyperdiploid acute lymphoblastic leukemia. Inability to accumulate high levels of methotrexate polyglutamates represents an important mechanism of methotrexate resistance. Recently, mutations in genes required to regulate the cell cycle have been implicated in methotrexate resistance through increasing expression of the gene for dihydrofolate reductase.