Intrinsic and acquired resistance to methotrexate in acute leukemia

Researchers are developing new drugs to treat diseases that no longer respond to methotrexate. Methotrexate is used to treat many types of cancer as well as rheumatoid arthritis, psoriasis and autoimmune diseases. It inhibits the enzyme dihydrofolate reductase, which ultimately inhibits DNA replication and causes cell death. However, the cells can become resistant to methotrexate by producing more of the enzyme or changing the transport and metabolism of methotrexate. Mutations in the gene for the enzyme have also been found in drug-resistant tumors. Methotrexate resistance can also occur if the retinoblastoma protein is defective.