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Cancer chemotherapy: targeting folic acid synthesis

Authors Hagner N, Joerger M

Published 19 November 2010 Volume 2010:2 Pages 293—301

DOI https://doi.org/10.2147/CMAR.S10043

Review by Single-blind

Peer reviewer comments 2


Nicole Hagner, Markus Joerger
Department of Medical Oncology, Cantonal Hospital, St Gallen, Switzerland

Abstract: Antifolates are structural analogs of folates, essential one-carbon donors in the synthesis of DNA in mammalian cells. Antifolates are inhibitors of key enzymes in folate metabolism, namely dihydrofolate reductase, β-glycinamide ribonucleotide transformylase, 5'-amino-4'-imidazolecarboxamide ribonucleotide transformylase, and thymidylate synthetase. Methotrexate is one of the earliest anticancer drugs and is extensively used in lymphoma, acute lymphoblastic leukemia, and osteosarcoma, among others. Pemetrexed has been approved in combination with cisplatin as first-line treatment for advanced non-squamous-cell lung cancer, as a single agent for relapsed non-small-cell lung cancer after platinum-containing chemotherapy, and in combination with cisplatin for the treatment of pleural mesothelioma. Raltitrexed is approved in many countries (except in the United States) for advanced colorectal cancer, but its utilization is mainly limited to patients intolerant to 5-fluorouracil. Pralatrexate has recently been approved in the United States for relapsed or refractory peripheral T-cell lymphoma. This article gives an overview of the cellular mechanism, pharmacology, and clinical use of classical and newer antifolates and discusses some of the main resistance mechanisms to antifolate drugs.

Keywords: antifolates, cancer, molecular pharmacology, pemetrexed, methotrexate, folate metabolism

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