Novel developments in the use of antimetabolites

Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):358-74. doi: 10.1080/15257770.2014.894197.


Antimetabolites are the most widely used and most efficacious group of anticancer drugs. Antimetabolites are also the oldest rationally designed anticancer drugs, targeted against RNA and DNA, and can, therefore, be considered as the first generation of targeted drugs. Unfortunately, resistance often develops, leading to the design of new antimetabolites, which either have a novel mechanism of action, bypass resistance or in combination enhance the effect of other drugs, such as another antimetabolite, other DNA, or protein kinase targeted anticancer drugs. Several novel antimetabolites are in clinical development. The cytidine-analog fluorocyclopentenylcytosine (RX-3117) is active in gemcitabine-resistant tumors and is activated by uridine-cytidine-kinase, can be incorporated into RNA and DNA and can downregulate DNA-methyltransferase-1. TAS-114 is a new generation dUTPase inhibitor. dUTPase normally prevents incorporation of dUTP and of the 5FU-nucleotide FdUTP into DNA. However, inhibition of dUTPase will enhance their incorporation, thereby increasing thymine-less cell-death. The formulation TAS-102 (trifluorothymidine and thymidine-phosphorylase-inhibitor) acts by incorporation into DNA and has shown efficacy in tumors progressing on 5FU therapy. Gemcitabine and cytarabine prodrugs were tested in model systems and have entered clinical evaluation. The elaidic-acid prodrugs of gemcitabine (CP-4126, CO101) and cytarabine (elacytarabine) failed in randomized Phase III studies. Two other gemcitabine prodrugs LY2334737 (gemcitabine with a valproic acid at the 5'-position) and NUC1031 (a 5'-arylphosphoamidate prodrug, with a side-chain at the 5'-phosphate) are in early clinical development. In summary, several novel antimetabolites show promise in clinical development, either because of a novel mechanism of action, or clever combination or by innovative prodrug design.

Keywords: Antimetabolites; TAS-102; TAS-114; deoxycytidine kinase; equilibrative nucleoside transporter; fluorocyclopentenyl cytosine; gemcitabine prodrugs; trifluorothymidine; uridine-cytidine kinase.

Publication types

  • Review

MeSH terms

  • Animals
  • Antimetabolites / metabolism
  • Antimetabolites / pharmacology*
  • Antimetabolites / therapeutic use
  • Drug Discovery / methods*
  • Drug Interactions
  • Humans
  • Prodrugs / metabolism


  • Antimetabolites
  • Prodrugs