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Special Issue "5-Fluorouracil"

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Synthesis".

Deadline for manuscript submissions: closed (15 October 2008)

Special Issue Editor

Guest Editor
Prof. Dr. Francesco Puoci (Website)

Dipartimento di Scienze Farmaceutiche, Università della Calabria, Edificio Polifunzionale, Arcavacata di Rende (CS) 87036, Italy
Fax: +39 0984 493298
Interests: molecularly imprinted polymers; functional materials for biomedical applications

Special Issue Information

Dear Colleagues,

Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains one of the most important anticancer agents. In 5-FU, the hydrogen atom at the 5-position of uracil is replaced by a fluorine atom and the molecule was designed to occupy the active sites of enzyme targets, thereby blocking metabolism in malignant cells. Although this antimetabolite is toxic, its efficacy makes it one of the most widely used agents against solid tumors. Numerous reports by the scientific community have been devoted to 5-FU, covering a wide range of topics: preparation of innovative formulations, synthesis of 5-FU derivatives, mechanism of action studies, etc. This special issue of Molecules aims to provide an overview of the current knowledge on this important chemotherapeutic agent, as well as focus on current strategies to improve therapeutic effectiveness of this drug in the treatment of advanced disease.

Dr Francesco Puoci
Guest Editor

Keywords

  • 5-fluorouracil (5-FU)
  • 5-FU analogues
  • fluorouracil derivatives
  • prodrugs

Published Papers (8 papers)

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Research

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Open AccessArticle Decreased Oxygen Transfer Capacity of Erythrocytes as a Cause of 5-Fluorouracil Related Ischemia
Molecules 2009, 14(1), 53-67; doi:10.3390/molecules14010053
Received: 15 October 2008 / Revised: 21 December 2008 / Accepted: 24 December 2008 / Published: 28 December 2008
Cited by 6 | PDF Full-text (889 KB) | HTML Full-text | XML Full-text
Abstract
cisplatin have similar effects on the erythrocyte membrane, thus eliminating those changes as a potential source of cardiotoxicity. On the contrary, 31P-NMR and polarography showed that the effects of these cytostatics on the intracellular milieu differ significantly. 5-FU provoked a pronounced [...] Read more.
cisplatin have similar effects on the erythrocyte membrane, thus eliminating those changes as a potential source of cardiotoxicity. On the contrary, 31P-NMR and polarography showed that the effects of these cytostatics on the intracellular milieu differ significantly. 5-FU provoked a pronounced decrease of the O2 level in blood and affected the metabolism of phosphate compounds, while cisplatin had no such effects. When combined these two drugs showed synergistic effects, which matches the higher frequency of cardiotoxicity of the combination relative to the sole application of 5-FU. Preliminary results acquired on blood of patients receiving cisplatin/5-FU therapy verified observations obtained ex vivo. These results open a possibility of applying NMR in preclinical trials of new drugs in order to predict their ischemic potential. Full article
(This article belongs to the Special Issue 5-Fluorouracil)
Open AccessArticle Influence of Spray-dried Hydroxyapatite-5-Fluorouracil Granules on Cell Lines Derived from Tissues of Mesenchymal Origin
Molecules 2008, 13(11), 2729-2739; doi:10.3390/molecules13112729
Received: 8 June 2008 / Revised: 9 October 2008 / Accepted: 24 October 2008 / Published: 1 November 2008
Cited by 7 | PDF Full-text (2930 KB) | HTML Full-text | XML Full-text
Abstract
In our previous work we described the preparation and characterization of spray dried hydroxyapatite micro granules loaded with 5-fluorouracil (5-FU). These loaded particles are used as a model drug delivery system (DDS). In this study we examined the in vitro response of [...] Read more.
In our previous work we described the preparation and characterization of spray dried hydroxyapatite micro granules loaded with 5-fluorouracil (5-FU). These loaded particles are used as a model drug delivery system (DDS). In this study we examined the in vitro response of two cell lines derived from different tissues to 5-FU loaded granules (LG). Both cell lines, either L929 cells of a mouse fibroblast lineage or cells originating from a rat osteosarcoma (ROS 17/2.8) showed a dose dependent decrease in cell proliferation in response to 5-FU-, either dissolved in the culture medium or loaded onto particles. The response of the two cell lines to loaded and nonloaded particles was different. The effect of LG and of a corresponding concentration of free 5-FU was practically the same for the ROS 17/2.8 cells indicating that ROS 17/2.8 cells were not affected by the carrier material. In contrast, L929 cells showed a slight decrease in cell proliferation also in the presence of granules not loaded with 5-FU. This is thought to be attributed to the inhibition of mitogenesis by phosphocitrates, already demonstrated in fibroblasts. In summary, we found that the loaded 5-FU kept its effectivity after the spray drying process and that the response towards the granules varied with cell type. This is the first step towards a tissue specific DDS. Full article
(This article belongs to the Special Issue 5-Fluorouracil)
Figures

Open AccessArticle Surface-enhanced Raman Spectral Measurements of 5-Fluorouracil in Saliva
Molecules 2008, 13(10), 2608-2627; doi:10.3390/molecules13102608
Received: 8 August 2008 / Revised: 16 October 2008 / Accepted: 20 October 2008 / Published: 22 October 2008
Cited by 23 | PDF Full-text (462 KB) | HTML Full-text | XML Full-text
Abstract
The ability of surface-enhanced Raman spectroscopy (SERS) to measure 5-fluorouracil (5-FU) in saliva is presented. The approach is based on the capacity of Raman spectroscopy to provide a unique spectral signature for virtually every chemical, and the ability of SERS to provide [...] Read more.
The ability of surface-enhanced Raman spectroscopy (SERS) to measure 5-fluorouracil (5-FU) in saliva is presented. The approach is based on the capacity of Raman spectroscopy to provide a unique spectral signature for virtually every chemical, and the ability of SERS to provide μg/mL sensitivity. A simple sampling method, that employed 1-mm glass capillaries filled with silver-doped sol-gels, was developed to isolate 5-FU from potential interfering chemical components of saliva and simultaneously provide SERSactivity. The method involved treating a 1 mL saliva sample with 1 mL of acetic acid, drawing 10 μL of sample into a SERS-active capillary by syringe, and then measuring the SER spectrum. Quality SER spectra were obtained for samples containing as little as 2 μg of 5-FU in 1 mL saliva. The entire process, the acid pretreatment, extraction and spectral measurement, took less than 5 minutes. The SERS of 5-fluorouridine and 5-fluoro-2’-deoxyuridine, two major metabolites of 5-FU, were also measured and shown to have unique spectral peaks. These measurements suggest that disposable SERS-active capillaries could be used to measure 5-FU and metabolite concentrations in chemotherapy patient saliva, thereby providing metabolic data that would allow regulating dosage. Tentative vibrational mode assignments for 5-FU and its metabolites are also given. Full article
(This article belongs to the Special Issue 5-Fluorouracil)
Figures

Open AccessArticle Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters
Molecules 2008, 13(7), 1441-1454; doi:10.3390/molecules13071441
Received: 12 June 2008 / Accepted: 27 June 2008 / Published: 28 June 2008
Cited by 29 | PDF Full-text (199 KB) | HTML Full-text | XML Full-text
Abstract
A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5′-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of [...] Read more.
A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5′-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 – 2.3 mM in Caco-2 and 2.0 – 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 – 5.31 x 10-6 cm/sec) and floxuridine (0.48 x 10-6 cm/sec) were much higher than that of 5-FU (0.038 x 10-6 cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy. Full article
(This article belongs to the Special Issue 5-Fluorouracil)

Review

Jump to: Research

Open AccessReview Novel Strategies to Improve the Anticancer Action of 5-Fluorouracil by Using Drug Delivery Systems
Molecules 2008, 13(10), 2340-2369; doi:10.3390/molecules13102340
Received: 22 April 2008 / Revised: 16 September 2008 / Accepted: 16 September 2008 / Published: 1 October 2008
Cited by 69 | PDF Full-text (717 KB)
Abstract
Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of the anticancer drug 5-fluorouracil have been devised. The target is always to provide the proper dose [...] Read more.
Because of the fundamental importance of new therapeutic routes for cancer treatment, a number of systems based on colloidal particles as vehicles for the delivery of the anticancer drug 5-fluorouracil have been devised. The target is always to provide the proper dose of the antitumor agent only at the desired locus of action, thus reducing the unwanted side effects. In this review, the main strategies and the more significant results in the development of 5-fluorouracil carriers for cancer treatment are discussed. Full article
(This article belongs to the Special Issue 5-Fluorouracil)
Open AccessReview Radiation- and Photo-induced Activation of 5-Fluorouracil Prodrugs as a Strategy for the Selective Treatment of Solid Tumors
Molecules 2008, 13(10), 2370-2384; doi:10.3390/molecules13102370
Received: 8 September 2008 / Revised: 22 September 2008 / Accepted: 22 September 2008 / Published: 1 October 2008
Cited by 16 | PDF Full-text (248 KB) | HTML Full-text | XML Full-text
Abstract
5-Fluorouracil (5-FU) is used widely as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers, although its clinical application is limited because 5-FU has gastrointestinal and hematological toxicity. Many groups are searching for prodrugs with functions [...] Read more.
5-Fluorouracil (5-FU) is used widely as an anticancer drug to treat solid cancers, such as colon, breast, rectal, and pancreatic cancers, although its clinical application is limited because 5-FU has gastrointestinal and hematological toxicity. Many groups are searching for prodrugs with functions that are tumor selective in their delivery and can be activated to improve the clinical utility of 5-FU as an important cancer chemotherapeutic agent. UV and ionizing radiation can cause chemical reactions in a localized area of the body, and these have been applied in the development of site-specific drug activation and sensitization. In this review, we describe recent progress in the development of novel 5-FU prodrugs that are activated site specifically by UV light and ionizing radiation in the tumor microenvironment. We also discuss the chemical mechanisms underlying this activation. Full article
(This article belongs to the Special Issue 5-Fluorouracil)
Figures

Open AccessReview Efficacy of the Oral Fluorouracil Pro-drug Capecitabine in Cancer Treatment: a Review
Molecules 2008, 13(8), 1897-1922; doi:10.3390/molecules13081897
Received: 30 May 2008 / Revised: 15 August 2008 / Accepted: 25 August 2008 / Published: 27 August 2008
Cited by 36 | PDF Full-text (289 KB) | HTML Full-text | XML Full-text
Abstract
Capecitabine (Xeloda®) was developed as a pro-drug of fluorouracil (FU), with the aim of improving tolerability and intratumor drug concentrations through its tumorspecific conversion to the active drug. The purpose of this paper is to review the available information on capecitabine, focusing [...] Read more.
Capecitabine (Xeloda®) was developed as a pro-drug of fluorouracil (FU), with the aim of improving tolerability and intratumor drug concentrations through its tumorspecific conversion to the active drug. The purpose of this paper is to review the available information on capecitabine, focusing on its clinical effectiveness against various carcinomas. Identification of all eligible English trails was made by searching the PubMed and Cochrane databases from 1980 to 2007. Search terms included capecitabine, Xeloda and cancer treatment. Nowadays, FDA has approved the use of capecitabine as a first line therapy in patients with metastatic colorectal cancer when single-agent fluoropyrimidine is preferred. The drug is also approved for use as a single agent in metastatic breast cancer patients who are resistant to both anthracycline and paclitaxel-based regimens or when further anthracycline treatment is contraindicated. It is also approved in combination with docetaxel after failure of prior anthracycline-based chemotherapy. In patients with prostate, pancreatic, renal cell and ovarian carcinomas, capecitabine as a single-agent or in combination with other drugs has also shown benefits. Improved tolerability and comparable efficacy, compared with the intravenous FU/LV combination, in addition to its oral administration, make capecitabine an attractive option for the treatment of several types of carcinomas. Full article
(This article belongs to the Special Issue 5-Fluorouracil)
Open AccessReview 5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies
Molecules 2008, 13(8), 1551-1569; doi:10.3390/molecules13081551
Received: 18 June 2008 / Revised: 1 July 2008 / Accepted: 15 July 2008 / Published: 5 August 2008
Cited by 103 | PDF Full-text (214 KB) | HTML Full-text | XML Full-text
Abstract
The purpose of this work is to review the published studies on the mechanisms of action and resistance of 5-fluorouracil. The review is divided into three main sections: mechanisms of anti-tumor action, studies of the resistance to the drug, and procedures for [...] Read more.
The purpose of this work is to review the published studies on the mechanisms of action and resistance of 5-fluorouracil. The review is divided into three main sections: mechanisms of anti-tumor action, studies of the resistance to the drug, and procedures for the identification of new genes involved in resistance with microarray techniques. The details of the induction and reversal of the drug resistance are also described. Full article
(This article belongs to the Special Issue 5-Fluorouracil)

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