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Resistance to antifolates

Rongbao Zhao1, I David Goldman

  • 1Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

Oncogene
|October 25, 2003
PubMed

Insights

Antifolate drugs are crucial in cancer treatment, but drug resistance can limit their effectiveness. Understanding resistance mechanisms helps develop new therapies and improve patient outcomes.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Antifolates represent the earliest antimetabolite chemotherapy agents, utilized for over 50 years.
  • Decades of research have elucidated their mechanisms of action and the cellular resistance pathways that emerge.
  • These principles inform the study of resistance to various antineoplastics targeting different cellular mechanisms.

Purpose of the Study:

  • To describe the mechanisms of intrinsic and acquired antifolate resistance.
  • To review strategies for overcoming resistance, including gene therapy for bone marrow protection.
  • To correlate antifolate pharmacology with clinical outcomes in pediatric cancer patients.

Main Methods:

  • Review of existing literature on antifolate mechanisms and resistance.
  • Analysis of cellular processes involved in drug transport, activation, and degradation.
  • Examination of target enzyme alterations and cofactor pool modulation.
  • Discussion of gene therapy applications and clinical outcome studies.

Main Results:

  • Antifolate resistance involves impaired drug uptake/transport, enhanced drug efflux, reduced activation (polyglutamylation), increased drug degradation, target enzyme mutations/overexpression, and altered tetrahydrofolate pools.
  • Gene therapy strategies are being developed to protect normal cells during antifolate treatment.
  • Clinical studies demonstrate a link between methotrexate's cellular pharmacology and treatment outcomes in pediatric cancers.

Conclusions:

  • Understanding antifolate resistance mechanisms is key to improving cancer chemotherapy.
  • Novel therapeutic strategies, including gene therapy, show promise for enhancing treatment efficacy and safety.
  • Clinical correlation studies are vital for optimizing antifolate-based treatment regimens in pediatric oncology.

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