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Anticancer antifolates: current status and future directions.

John J McGuire1

  • 1Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. John.McGuire@RoswellPark.edu

Current Pharmaceutical Design
|October 8, 2003
PubMed
Summary
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Antifolate anticancer drugs, like methotrexate, target dihydrofolate reductase. Newer antifolates selectively inhibit thymidylate synthase or purine synthesis, expanding cancer treatment options, including for colon cancer.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Antifolates are a cornerstone of antimetabolite chemotherapy, with methotrexate (MTX) being the primary agent since the mid-20th century.
  • MTX inhibits dihydrofolate reductase (DHFR), crucial for DNA synthesis, but its use is limited by toxicity and tumor spectrum.
  • Efforts to develop more selective antifolates are driven by understanding MTX's mechanism, including transport, DHFR inhibition, and polyglutamylation.

Purpose of the Study:

  • To review the development of antifolate anticancer agents.
  • To explore the rationale behind designing new antifolates targeting specific folate-dependent pathways.
  • To highlight the emergence of novel antifolates with improved selectivity and broader tumor applicability.

Main Methods:

Related Experiment Videos

  • Review of historical development and mechanistic studies of antifolates.
  • Analysis of structure-activity relationships and design strategies for novel antifolate enzyme inhibitors.
  • Summary of clinical trial outcomes for new antifolate agents.

    • Main Results:

    • Early antifolates like aminopterin and MTX showed efficacy but had limitations.
    • Development of classical and nonclassical DHFR inhibitors did not surpass MTX.
    • Newer antifolates targeting thymidylate synthase (TMPS) and purine synthesis enzymes have shown promise.
    • Raltitrexed (Tomudex), a TMPS inhibitor, is approved for colon cancer, extending antifolate utility.

    Conclusions:

    • Understanding antifolate mechanisms has enabled rational drug design.
    • Targeting specific folate pathways, like TMPS, offers therapeutic advantages over broad DHFR inhibition.
    • Continued research into novel antifolates with enhanced delivery and multiple pathway inhibition is ongoing.