RESISTANCE MECHANISMS TO METHOTREXATE IN TUMORS

The mechanisms of intrinsic and acquired resistance to methotrexate (M ITX) in human tumors are reviewed herein, In blasts from patients with acute lymphocytic leukemia, resistance mechanisms found are decreased uptake and increased dihydrofolate reductase (DHFR) activity, A major cause of intrinsic resistance to MTX in soft tissue sarcoma cells and in acute myelocytic leukemia appears to be a lack of drug retention, due mainly to low levels of polyglutamylation. A novel association bet ween lack of the retinoblastoma protein and intrinsic MTX resistance h as been found, This has been attributed to an increase in DHFR activit y, due to an increased rate of transcription of this gene, stimulated by an increase in Levels of free E2F, not sequestered by hypophosphory lated retinoblastoma protein.