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The basis for intrinsic drug resistance or sensitivity to methotrexate
J R Bertino1, J Lin, G Pizzorno
1Laboratory of Molecular Pharmacology, Memorial-Sloan Kettering Cancer Center, New York, N.Y. 10021.
Abstract:
Natural resistance to MTX in three different types of malignant cells is discussed. Two causes of resistance found were impaired drug uptake and impaired polyglutamylation. These resistance mechanisms have also been described to occur in cell lines with acquired resistance to this drug. In cells with acquired drug resistance, these phenotypic changes may reflect mutations in genes associated with transport of MTX or the enzyme DHFR, or in some circumstances reversion of the cell to a different phenotype without a mutational event. In cells with intrinsic resistance, the genetic mechanism responsible for these phenotypes is not known. Alternate treatment programs, e.g., with TMTX, or with TMTX and CPG2, a folate depleting enzyme, are under evaluation for these MTX resistant neoplasms.
Insights
Natural resistance to methotrexate (MTX) in cancer cells stems from impaired drug uptake and polyglutamylation. The genetic basis for this intrinsic resistance remains unknown, prompting evaluation of alternative therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Methotrexate (MTX) is a key chemotherapy agent.
- Drug resistance can be intrinsic (natural) or acquired.
- Understanding resistance mechanisms is crucial for effective cancer treatment.
Purpose of the Study:
- To investigate the causes of natural resistance to MTX in malignant cells.
- To compare intrinsic resistance mechanisms with those of acquired resistance.
- To explore potential alternative treatments for MTX-resistant cancers.
Main Methods:
- Analysis of MTX uptake in three types of malignant cells.
- Assessment of MTX polyglutamylation levels.
- Review of genetic factors associated with drug resistance.
Main Results:
- Impaired drug uptake and impaired polyglutamylation were identified as causes of natural MTX resistance.
- These mechanisms are similar to those observed in acquired MTX resistance.
- The genetic underpinnings of intrinsic resistance are currently unknown.
Conclusions:
- Intrinsic MTX resistance in cancer involves impaired drug handling at the cellular level.
- Further research is needed to elucidate the genetic basis of intrinsic resistance.
- Alternative treatment strategies, including TMTX and CPG2, are being explored for MTX-resistant neoplasms.