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Resistance Mechanisms to Methotrexate in Tumors
1Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, USA.
Abstract:
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.
Insights
Mechanisms of methotrexate (MTX) resistance in human tumors include decreased drug uptake and retention. A novel finding links retinoblastoma protein loss to increased dihydrofolate reductase (DHFR) activity and MTX resistance.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Methotrexate (MTX) is a key chemotherapy agent.
- Understanding resistance mechanisms is crucial for effective cancer treatment.
- Intrinsic and acquired resistance to MTX poses a significant clinical challenge.
Purpose of the Study:
- To review the known mechanisms of MTX resistance in human tumors.
- To identify novel associations contributing to MTX resistance.
Main Methods:
- Literature review of MTX resistance mechanisms.
- Analysis of resistance in acute lymphocytic leukemia, soft tissue sarcoma, and acute myelocytic leukemia.
- Investigation of drug retention, polyglutamylation, and protein interactions.
Main Results:
- Decreased MTX uptake and increased dihydrofolate reductase (DHFR) activity are observed in acute lymphocytic leukemia.
- Low polyglutamylation levels contribute to poor MTX retention in soft tissue sarcoma and acute myelocytic leukemia.
- A novel association between retinoblastoma protein loss and intrinsic MTX resistance was identified.
Conclusions:
- MTX resistance involves multiple mechanisms including drug transport, metabolism, and target enzyme activity.
- Retinoblastoma protein deficiency enhances DHFR transcription, leading to MTX resistance.
- Further research into these mechanisms can guide the development of overcoming MTX resistance strategies.