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Related Experiment Videos

Design and rationale for novel antifolates.

J R Bertino1, A Sobrero, E Mini

  • 1Department of Medicine, Yale University School of Medicine, New Haven, CT.

NCI Monographs : a Publication of the National Cancer Institute
|January 1, 1987
PubMed
Summary

New antifolate drugs aim for better cancer selectivity and effectiveness against methotrexate-resistant tumors. Trimetrexate (TMQ) shows promise, utilizing a unique uptake mechanism for high intracellular levels in leukemia cells.

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Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Antifolate drug development seeks improved selectivity and efficacy against resistant cancers.
  • Dihydrofolate reductase (DHFR) has been a primary target, but other folate-dependent enzymes are also crucial.
  • Tumor-specific DHFR inhibition is unlikely; exploiting drug transport offers a promising strategy.

Purpose of the Study:

  • To develop novel antifolate agents with enhanced selectivity and efficacy.
  • To overcome intrinsic or acquired resistance to methotrexate (MTX).
  • To explore alternative drug targets and transport mechanisms for antifolates.

Main Methods:

  • Investigating novel antifolate structures targeting DHFR and other folate-dependent enzymes.
  • Evaluating drug transport mechanisms, including MTX-independent pathways.

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  • Assessing the effectiveness of new antifolates against resistant tumor models.

    • Main Results:

    • Triazinate (TZT) demonstrated that antifolate transport can be exploited for selective toxicity.
    • A second generation of nonclassical folate antagonists, including trimetrexate (TMQ), has been developed.
    • Trimetrexate (TMQ) utilizes an MTX-independent uptake system, achieving high intracellular concentrations in leukemia cells.

    Conclusions:

    • Exploiting drug transport mechanisms is a viable strategy for developing selective and effective antifolates.
    • Trimetrexate (TMQ) represents a promising nonclassical antifolate with potential against MTX-resistant cancers.
    • Further clinical evaluation of trimetrexate (TMQ) is warranted for its efficacy in leukemia treatment.