Abstract
The fluoropyrimidines were first synthesised nearly 50 years ago as rationally designed anti-cancer agents. Their target was pyrimidine and hence DNA synthesis. 5-Fluorouracil has been the most extensively used in a wide variety of malignancies. In more recent years a fuller understanding of the pharmacokinetics of these agents has lead to their utilisation as more effective and versatile anti-cancer drugs than might have been initially envisaged. This in part has occurred due to recognition of the schedule dependency of efficacy of 5-FU and modulation of its activity by leucovorin. However the development of novel fluropyrimidines such as capcetabine, UFT, and eniluracil which can be administered orally, has offered equal if not superior efficacy with improved tolerability and patient acceptance. It is now recognised that enzyme polymorphisms and heterogeneity of expression of key molecules are important determinants of the pharmacokinetic handling and pharmacodynamic effects of these drugs in individual patients. Further characterisation of such interindividual and inter-tumoral variability, for example in enzymes such as DPD and thymidine phosphorylase is ongoing. This work offers the promise of improvements in efficacy and tolerability by the process of individualisation of chemotherapy (for both patient and tumour). In contrast to the advances made in the understanding of the pharmacokinetics, less progress has been made in Fluropyrimidine pharmacodynamics. The inhibition of thymidylate synthetase by dFUMP and thereby dTMP and DNA synthesis is thought to be the critical mechanism. The incorporation of FUTP and dFUTP into RNA and DNA are also postulated to be of importance. While these events have been well defined, exactly how they lead to cell death is less clearly understood. Similarly, the mechanism of selective cancer cell cytotoxicity is not well understood. Pharmacokinetics and cell cycle kinetics provide a partial explanation. There is some evidence to suggest that the most important factor in determining cytotoxicity is the cellular response to fluoropyrimidine induced biochemical abnormalities rather than the lesions themselves. In this hypothesis the difference in response between normal and cancer cells is of critical importance. Further improvements in efficacy and tolerability could be made by elucidation of the molecular mechanisms behind this process. This knowledge in combination with the advances already made (and ongoing) in pharmacokinetics may allow the full potential of fluoropyrimidines as anti-cancer agents to be realised in the future.
Keywords: fluropyrimidines, cytotoxic drugs, oncogenes, tumour suppresser genes
Current Cancer Drug Targets
Title: Novel Fluoropyrimidines: Improving the Efficacy and Tolerability of Cytotoxic Therapy
Volume: 4 Issue: 2
Author(s): Russell D. Petty and J. Cassidy
Affiliation:
Keywords: fluropyrimidines, cytotoxic drugs, oncogenes, tumour suppresser genes
Abstract: The fluoropyrimidines were first synthesised nearly 50 years ago as rationally designed anti-cancer agents. Their target was pyrimidine and hence DNA synthesis. 5-Fluorouracil has been the most extensively used in a wide variety of malignancies. In more recent years a fuller understanding of the pharmacokinetics of these agents has lead to their utilisation as more effective and versatile anti-cancer drugs than might have been initially envisaged. This in part has occurred due to recognition of the schedule dependency of efficacy of 5-FU and modulation of its activity by leucovorin. However the development of novel fluropyrimidines such as capcetabine, UFT, and eniluracil which can be administered orally, has offered equal if not superior efficacy with improved tolerability and patient acceptance. It is now recognised that enzyme polymorphisms and heterogeneity of expression of key molecules are important determinants of the pharmacokinetic handling and pharmacodynamic effects of these drugs in individual patients. Further characterisation of such interindividual and inter-tumoral variability, for example in enzymes such as DPD and thymidine phosphorylase is ongoing. This work offers the promise of improvements in efficacy and tolerability by the process of individualisation of chemotherapy (for both patient and tumour). In contrast to the advances made in the understanding of the pharmacokinetics, less progress has been made in Fluropyrimidine pharmacodynamics. The inhibition of thymidylate synthetase by dFUMP and thereby dTMP and DNA synthesis is thought to be the critical mechanism. The incorporation of FUTP and dFUTP into RNA and DNA are also postulated to be of importance. While these events have been well defined, exactly how they lead to cell death is less clearly understood. Similarly, the mechanism of selective cancer cell cytotoxicity is not well understood. Pharmacokinetics and cell cycle kinetics provide a partial explanation. There is some evidence to suggest that the most important factor in determining cytotoxicity is the cellular response to fluoropyrimidine induced biochemical abnormalities rather than the lesions themselves. In this hypothesis the difference in response between normal and cancer cells is of critical importance. Further improvements in efficacy and tolerability could be made by elucidation of the molecular mechanisms behind this process. This knowledge in combination with the advances already made (and ongoing) in pharmacokinetics may allow the full potential of fluoropyrimidines as anti-cancer agents to be realised in the future.
Export Options
About this article
Cite this article as:
Petty D. Russell and Cassidy J., Novel Fluoropyrimidines: Improving the Efficacy and Tolerability of Cytotoxic Therapy, Current Cancer Drug Targets 2004; 4 (2) . https://dx.doi.org/10.2174/1568009043481533
DOI https://dx.doi.org/10.2174/1568009043481533 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Related Books

- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Rapid Characterization of a Novel Taspine Derivative-HMQ1611 Binding to EGFR by a Cell Membrane Chromatography Method
Combinatorial Chemistry & High Throughput Screening EBV-Related Malignancies, Outcomes and Novel Prevention Strategies
Infectious Disorders - Drug Targets Development of Patents and Clinical Trials on Regenerative Therapy: Gene Therapy
Recent Patents on Regenerative Medicine Occurrence and Biological Properties of Sphingolipids - A Review
Current Nutrition & Food Science Editorial
Current Nutrition & Food Science Editorial (Hot Topic: Exploring Molecular and Clinical Management of Patients in the Follow Up of the HPV Related Uterine Lesions)
Current Pharmaceutical Design Therapeutic Study of Phytochemicals Against Cancer and Alzheimer’s Disease Management
Current Drug Metabolism TGF-β Signal Transduction in Pancreatic Carcinoma Cells is Sensitive to Inhibition by the Src Tyrosine Kinase Inhibitor AZM475271
Anti-Cancer Agents in Medicinal Chemistry Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents
Current Medicinal Chemistry Applications of Protein Microarray Technology
Combinatorial Chemistry & High Throughput Screening Biodistribution of Lipid Nanoparticles: A Comparative Study of Pulmonary versus Intravenous Administration in Rats
Current Radiopharmaceuticals Lipid-Protamine-DNA-Mediated Antigen Delivery
Current Drug Delivery Ethnic Differences in Pharmacogenetically Relevant Genes
Current Drug Targets Design, Synthesis and Biological Evaluation of 1H-1,2,3-Triazole-Linked-1H-Dibenzo[b,h]xanthenes as Inductors of ROS-Mediated Apoptosis in the Breast Cancer Cell Line MCF-7
Medicinal Chemistry Gastric Tract Infections Detection and Classification from Wireless Capsule Endoscopy using Computer Vision Techniques: A Review
Current Medical Imaging Genomics and Proteomics of Nucleoside Transporters
Current Pharmacogenomics Stimulation of Tumor-Specific Immunity by p5 HER-2/neu Generated Peptide Encapsulated in Nano-liposomes with High Phase Transition Temperature Phospholipids
Current Drug Delivery Facile Synthesis of Hollow Mesoporous Hydroxyapatite Nanoparticles for Intracellular Bio-imaging
Current Nanoscience Identification of Essential 2D and 3D Chemical Features for Discovery of the Novel Tubulin Polymerization Inhibitors
Current Topics in Medicinal Chemistry Strategies for the Design of Potent and Selective Kinase Inhibitors
Current Pharmaceutical Design