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Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells

Alan Kambiz Fotoohi1, Freidoun Albertioni

  • 1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

Leukemia & Lymphoma
|February 26, 2008
PubMed

Insights

Antifolates like methotrexate (MTX) are crucial in leukemia treatment. Understanding resistance mechanisms, including drug uptake, metabolism, and efflux, is key to improving antifolate efficacy against cancer.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Antifolates, a class of antimetabolites, have been used for decades in treating malignancies, particularly leukemia.
  • Despite their long history, a complete understanding of their mechanisms of action and resistance in leukemic cells remains an active area of research.

Purpose of the Study:

  • To comprehensively review factors influencing antifolate efficacy in leukemic cells.
  • To detail known mechanisms of resistance to methotrexate (MTX).
  • To explore strategies for overcoming MTX resistance.

Main Methods:

  • Literature review and synthesis of existing research on antifolate mechanisms and resistance.
  • Analysis of factors affecting antifolate efficacy, including pharmacokinetic properties and cellular processes.
  • Discussion of specific resistance pathways and potential therapeutic interventions.

Main Results:

  • Key factors contributing to MTX resistance include impaired transmembrane uptake, increased drug efflux, and reduced intracellular polyglutamation.
  • Alterations in target enzyme activity, increased intracellular folate pools, and the role of 7-hydroxymethotrexate also influence MTX response.
  • Multiple cellular mechanisms contribute to tolerance to antifolate cytocidal effects.

Conclusions:

  • Understanding the multifaceted mechanisms of antifolate resistance is crucial for optimizing cancer therapy.
  • Developing strategies to overcome these resistance pathways can enhance the effectiveness of antifolates in leukemia treatment.
  • Further research is needed to fully elucidate and target antifolate resistance in malignancies.

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