Open AccessResistance Mechanisms to Methotrexate in Tumors
Author(s) -
Bertino J. R.,
Göker E.,
Gorlick R.,
Li W. W.,
Banerjee D.
Publication year - 1996
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.140005
Subject(s) - biology , retinoblastoma , methotrexate , dihydrofolate reductase , cancer research , retinoblastoma protein , drug resistance , leukemia , acute lymphocytic leukemia , osteosarcoma , immunology , gene , cell cycle , biochemistry , genetics , lymphoblastic leukemia
The mechanisms of intrinsic and acquired resistance to methotrexate (MTX) 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 between lack of the retinoblastoma protein and intrinsic MTX resistance has been found. This has been attributed to an increase in DHFR activity, due to an increased rate of transcription of this gene, stimulated by an increase in levels of free E2F, not sequestered by hypophosphorylated retinoblastoma protein.