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Updated: Oct 11, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Determinants of resistance to antifolates: biochemical phenotypes, their frequency of occurrence and circumvention

F M Sirotnak1

  • 1Memorial Sloan-Kettering Cancer Center, Laboratory for Molecular Therapeutics, New York, NY 10021.

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

Insights

Tumor cells develop resistance to antifolates through diverse biochemical changes affecting drug transport and targets like dihydrofolate reductase (DHFR). New drug design strategies analyze these resistance mechanisms for effective circumvention.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cancer Biology

Background:

  • Acquired resistance in tumor cells to antifolates is a significant clinical challenge.
  • Common resistance mechanisms involve alterations in membrane transport and the primary target, dihydrofolate reductase (DHFR).

Purpose of the Study:

  • To explore diverse biochemical alterations contributing to antifolate resistance.
  • To describe novel drug design approaches for circumventing acquired antifolate resistance.

Main Methods:

  • Analysis of quantitative and qualitative changes in membrane transport and DHFR.
  • Investigation of thymidylate synthase activity and 4-aminofolate polyglutamylation.
  • Kinetic analysis of biochemical phenotypes and structure-activity relationships.

Main Results:

  • Identified diverse biochemical alterations, including changes in DHFR, thymidylate synthase, and folate metabolism.
  • Developed drug design strategies incorporating kinetic and structure-activity analyses.

Conclusions:

  • Understanding the spectrum of biochemical resistance phenotypes is crucial for effective antifolate therapy.
  • New drug design approaches considering population genetics and resistance phenotypes can overcome acquired antifolate resistance.

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