Antifolates in cancer therapy: Structure, activity and mechanisms of drug resistance

Nitzan Gonen, Yehuda G. Assaraf

Research output: Contribution to journalArticlepeer-review

353 Scopus citations


In the past 65 years, antifolates targeting folate metabolism played a pivotal role in drug treatment of malignant, microbial, parasitic and chronic inflammatory diseases. Drug discovery of novel antifolates with improved properties and superior activities remains an attractive strategy both in academia and in the pharmaceutical industry. Among novel antifolates are pemetrexed which primarily targets thymidylate synthase as well as pralatrexate which blocks dihydrofolate reductase, and displays enhanced transport and cellular retention properties. The present review describes the evolution and pharmacological activity of antifolates and prospects for the development of the next generation antifolates. Pre-clinical and clinical studies identified a plethora of mechanisms of antifolate resistance that are a primary hindrance to curative cancer chemotherapy; these are frequently associated with qualitative and/or quantitative alterations in influx and/or efflux transporters of antifolates and in folate-dependent enzymes. Current advances including for example the deciphering of the dominant folate transporter proton-coupled folate transporter (PCFT/SLC46A1) facilitated the synthesis of experimental antifolates aimed at selectively targeting solid tumor cells, which reside in an acidic microenvironment where PCFT supposedly functions optimally. Moreover, drugs that are structurally and mechanistically distinct from folates were conjugated to folic acid (e.g. Vintafolide/EC145, a folic acid desacetylvinblastine conjugate) to facilitate endocytosis via the folate receptor (FR) which is markedly overexpressed in various solid tumors. In an alternative approach, novel antifolates selectively targeting the FR but not other folate transporters are being developed (e.g. BGC 945). Hence, targeting mechanisms of antifolate-resistance could facilitate the development of rationally-based novel antifolates and strategies that overcome chemoresistance.

Original languageEnglish
Pages (from-to)183-210
Number of pages28
JournalDrug Resistance Updates
Issue number4
StatePublished - Aug 2012
Externally publishedYes

Bibliographical note

Copyright © 2012 Elsevier Ltd. All rights reserved.


  • Antifolates
  • Cancer
  • Chemotherapy
  • Drug resistance
  • Folate pools
  • Folate-dependent enzymes
  • Folates
  • Influx and efflux transporters


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