Cancer chemotherapy: targeting folic acid synthesis

Our plain-English summary of Cancer chemotherapy: targeting folic acid synthesis, by N. Hagner, M. Joerger (Cancer Management and Research, 2010).

The study

• Authors: N. Hagner, M. Joerger
• Journal: Cancer Management and Research
• Published: 2010;2:293-301
• Cited by: 118 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article was a review, not a new study. It gave an overview of antifolates, cancer drugs that resemble the vitamin folate and block enzymes that cells need to make DNA. It described how these drugs enter cells, how cancers become resistant to them, and the pharmacology and clinical use of methotrexate, raltitrexed, pralatrexate, pemetrexed and several other antifolates. The article did not study asbestos exposure. Its link to asbestos-related disease was pemetrexed, which the authors reported has been approved in combination with cisplatin for treating pleural mesothelioma. They wrote that patients on pemetrexed routinely receive folic acid and vitamin B12, which has been shown to reduce potentially fatal bone-marrow suppression. They also wrote that kidney function needs monitoring because pemetrexed is often combined with cisplatin, which can harm the kidneys. The authors concluded that pemetrexed's approvals, including first-line treatment of malignant pleural mesothelioma, had substantially added to the clinical importance of antifolates. They expected future treatment to use genetic markers, such as the level of the enzyme thymidylate synthetase (TYMS) in tumors.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of the mechanism, pharmacology, resistance and clinical use of antifolate cancer drugs
• Who was studied: No study population; the article reviews published research on antifolate drugs
• Exposure: No asbestos exposure was studied. The subject is antifolate drugs, including methotrexate, raltitrexed, pralatrexate, lometrexol, edatrexate, talotrexin, trimetrexate, piritrexim, nolatrexed and pemetrexed.
• Main results:
  • The review reports that pemetrexed has been approved in combination with cisplatin for the treatment of pleural mesothelioma.
  • For pemetrexed, the review describes routine supplementation with oral folic acid 0.5 mg/day and intramuscular vitamin B12 1 mg every 9 weeks, which it says has been shown to reduce the incidence of potentially fatal myelosuppression (bone-marrow suppression).
  • The review states that kidney function should be monitored because pemetrexed is often combined with cisplatin, which can damage the kidneys.
  • The review reports that homocysteine, a marker of the body's folate status, predicted severe pemetrexed-related toxicity in a clinical study it cited.
• The authors' conclusion: The authors concluded that the approvals of pemetrexed, including first-line treatment of malignant pleural mesothelioma, had substantially added to the clinical importance of antifolates in oncology. They expected new strategies to include pharmacogenetic markers such as tumoral TYMS expression.

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Antifolate, Pemetrexed (Alimta), Cisplatin, Lung Cancer, Pleural Mesothelioma, Raltitrexed, Colorectal Cancer.

Related studies

• Development of a Pemetrexed/Folic Acid Nanoformulation: Synthesis, Characterization, and Efficacy in a Murine Colorectal Cancer Model — J.G. Rosch, A.N. DuRoss, et al. (2020)
• Folic acid phenotype (FAP) is a superior biomarker predicting response to pemetrexed-based chemotherapy in malignant pleural mesothelioma — F.D. Mairinger, C. Vollbrecht, et al. (2017)
• An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity — A.R. Minchom, K. Saksornchai, et al. (2014)
• Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives — Y.S. Choi, Y.J. Kim, et al. (2024)
• Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient pleural mesothelioma — S. Karnan, A. Ota, et al. (2026)
• Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma — M. Cioce, C. Canino, et al. (2021)

Browse more research in Cancer Management and Research, or return to medical research.